Amidoethyl azole orexin receptor antagonists

ABSTRACT

The present invention is directed to amidoethyl azole compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase application under 35 U.S.C. §371 of PCT Application No. PCT/US2015/066545, filed Dec. 18, 2015, whichclaims priority from PCT Application No. PCT/CN2014/094590, filed Dec.23, 2014.

BACKGROUND OF THE INVENTION

The orexins (hypocretins) comprise two neuropeptides produced in thehypothalamus: orexin A (OX-A) (a 33 amino acid peptide) and the orexin B(OX-B) (a 28 amino acid peptide) (Sakurai T. et al., Cell, 1998, 92,573-585). Orexins are found to stimulate food consumption in ratssuggesting a physiological role for these peptides as mediators in thecentral feedback mechanism that regulates feeding behavior (Sakurai T.et al., Cell, 1998, 92, 573-585). Orexins regulate states of sleep andwakefulness opening potentially novel therapeutic approaches fornarcoleptic or insomniac patients (Chemelli R. M. et al., Cell, 1999,98, 437-451). Orexins have also been indicated as playing a role inarousal, reward, learning and memory (Harris, et al., Trends Neurosci.,2006, 29 (10), 571-577). Two orexin receptors have been cloned andcharacterized in mammals. They belong to the super family of G-proteincoupled receptors (Sakurai T. et al., Cell, 1998, 92, 573-585): theorexin-1 receptor (OX or OX1R) is selective for OX-A and the orexin-2receptor (OX2 or OX2R) is capable of binding OX-A as well as OX-B. Thephysiological actions in which orexins are presumed to participate arethought to be expressed via one or both of OX1 receptor and OX2 receptoras the two subtypes of orexin receptors.

SUMMARY OF THE INVENTION

The present invention is directed to amidoethyl azole compounds whichare antagonists of orexin receptors. The present invention is alsodirected to uses of the compounds described herein in the potentialtreatment or prevention of neurological and psychiatric disorders anddiseases in which orexin receptors are involved. The present inventionis also directed to compositions comprising these compounds. The presentinvention is also directed to uses of these compositions in thepotential prevention or treatment of such diseases in which orexinreceptors are involved.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of the formula I:

wherein:

-   A is selected from the group consisting of phenyl, naphthyl and    heteroaryl;-   X is N or CH;-   each of R^(1a), R^(1b) and R^(1c) is independently selected from the    group consisting of:    -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) —(C═O)_(m)—O_(n)—C₁₋₆alkyl, where m is 0 or 1, n is 0 or 1        (wherein if m is 0 or n is 0, a bond is present) and where the        alkyl is unsubstituted or substituted with one to three        substituents independently selected from R⁴,    -   (5) —(C═O)_(m)—O_(n)—C₃₋₆cycloalkyl, where the cycloalkyl is        unsubstituted or substituted with one to three substituents        independently selected from R⁴,    -   (6) —(C═O)_(m)—C₂₋₄alkenyl, where the alkenyl is unsubstituted        or substituted with one to three substituents independently        selected from R⁴,    -   (7) —(C═O)_(m)—C₂₋₄alkynyl, where the alkynyl is unsubstituted        or substituted with one to three substituents independently        selected from R⁴,    -   (8) —(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-naphthyl, where        the phenyl or naphthyl is unsubstituted or substituted with one        to three substituents independently selected from R⁴,    -   (9) —(C═O)_(m)—O_(n)-heterocycle, where the heterocycle is        unsubstituted or substituted with one to three substituents        independently selected from R⁴,    -   (10) —(C═O)_(m)—NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are independently        selected from the group consisting of:        -   (a) hydrogen,        -   (b) C₁₋₆alkyl, which is unsubstituted or substituted with            R⁴,        -   (c) C₃₋₆alkenyl, which is unsubstituted or substituted with            R⁴,        -   (d) C₃₋₆alkynyl, which is unsubstituted or substituted with            R⁴,        -   (e) C₃₋₆cycloalkyl which is unsubstituted or substituted            with R⁴,        -   (f) phenyl, which is unsubstituted or substituted with R⁴,            and        -   (g) heterocycle, which is unsubstituted or substituted with            R⁴,    -   (11) —S(O)₂—NR¹⁰R¹¹,    -   (12) —S(O)_(q)—R¹², where q is 0, 1 or 2 and where R¹² is        selected from the definitions of R¹⁰ and R¹¹,    -   (13) —CO₂H,    -   (14) —CN, and    -   (15) —NO₂;        R³ is selected from hydrogen and C₁₋₆alkyl;        R⁴ is selected from the group consisting of:    -   (1) hydroxyl,    -   (2) halogen,    -   (3) C₁₋₆alkyl,    -   (4) —C₃₋₆cycloalkyl,    -   (5) —O—C₁₋₆alkyl,    -   (6) —O(C═O)—C₁₋₆alkyl,    -   (7) —NH₂,    -   (8) —NH—C₁₋₆alkyl,    -   (9) —NO₂,    -   (10) phenyl,    -   (11) heterocycle,    -   (12) —CO₂H, and    -   (13) —CN;        R⁵ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) halogen,    -   (3) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen or hydroxyl,    -   (4) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, and    -   (5) —(C═O)—O—C₁₋₆alkyl;        R⁶ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) halogen,    -   (3) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen or hydroxyl,    -   (4) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, and    -   (5) —(C═O)—O—C₁₋₆alkyl;        or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIa:

wherein A, R^(1a), R^(1b), R^(1c), R³, R⁵ and R⁶ are defined herein; ora pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIa′:

wherein R^(1a), R^(1b), R³, R⁵ and R⁶ are defined herein; or apharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIa″:

wherein R^(1a), R³, R⁵ and R⁶ are defined herein; or a pharmaceuticallyacceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIb:

wherein R^(1a), R^(1b), R³, R⁵ and R⁶ are defined herein; or apharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIb′:

wherein R^(1a), R³, R⁵ and R⁶ are defined herein; or a pharmaceuticallyacceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIc:

wherein R^(1a), R^(1b), R², R³, R⁵ and R⁶ are defined herein; or apharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIc′:

wherein R^(1a), R^(1b), R³, R⁵ and R⁶ are defined herein; or apharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIb″:

wherein R^(1a), R³, R⁵ and R⁶ are defined herein; or a pharmaceuticallyacceptable salt thereof.

An embodiment of the present invention includes compounds wherein A isselected from phenyl, pyridyl, thiophenyl, thiazolyl, isothiazolyl, andpyrazolyl. An embodiment of the present invention includes compoundswherein A is phenyl. An embodiment of the present invention includescompounds wherein A is pyridyl. An embodiment of the present inventionincludes compounds wherein A is thiophenyl. An embodiment of the presentinvention includes compounds wherein A is thiazolyl. An embodiment ofthe present invention includes compounds wherein A is isothiazolyl. Anembodiment of the present invention includes compounds wherein A ispyrazolyl.

An embodiment of the present invention includes compounds wherein X isN. An embodiment of the present invention includes compounds wherein Xis CH.

An embodiment of the present invention includes compounds whereinR^(1a), R^(1b) and R^(1c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl,    -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl,    -   (6) heteroaryl, wherein heteroaryl is selected from imidazolyl,        indolyl, oxazolyl, pyridyl, pyrrolyl, pyrimidinyl, tetrazolyl,        and triazolyl, which is unsubstituted or substituted with        halogen, hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂,    -   (7) phenyl, which is unsubstituted or substituted with halogen,        hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂,    -   (8) —O-phenyl, which is unsubstituted or substituted with        halogen, hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂,    -   (9) —CN, and    -   (10) —NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)(C₁₋₆alkyl), which is        unsubstituted or substituted with halogen, hydroxyl, C₁₋₆alkyl,        and —O—C₁₋₆alkyl.

An embodiment of the present invention includes compounds whereinR^(1a), R^(1b) and R^(1c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl,    -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl,    -   (6) —CN, and    -   (7) heteroaryl, wherein heteroaryl is selected from imidazolyl,        indolyl, oxazolyl, pyridyl, pyrrolyl, pyrimidinyl, tetrazolyl,        and triazolyl, which is unsubstituted or substituted with        halogen, hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂.

An embodiment of the present invention includes compounds whereinR^(1a), R^(1b) and R^(1c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen,    -   (4) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen,    -   (5) —CN, and    -   (6) heteroaryl, wherein heteroaryl is selected from imidazolyl,        indolyl, oxazolyl, pyridyl, pyrrolyl, pyrimidinyl, tetrazolyl,        and triazolyl.

An embodiment of the present invention includes compounds wherein R^(1c)is hydrogen, and R^(1a) and R^(1b) are independently selected from thegroup consisting of:

-   -   (1) hydrogen,    -   (2) fluoro,    -   (3) chloro,    -   (4) bromo,    -   (5) methyl,    -   (6) ethyl,    -   (7) methoxy,    -   (8) trifluoromethyl, and    -   (9) heteroaryl, wherein heteroaryl is selected from imidazolyl,        indolyl, oxazolyl, pyridyl, pyrrolyl, pyrimidinyl, tetrazolyl,        and triazolyl.

An embodiment of the present invention includes compounds wherein R^(1c)is hydrogen, and R^(1a) and R^(1b) are independently selected from thegroup consisting of:

-   -   (1) hydrogen,    -   (2) fluoro,    -   (3) chloro,    -   (4) methyl,    -   (5) methoxy,    -   (6) tetrazolyl, and    -   (7) triazolyl.

An embodiment of the present invention includes compounds wherein R³ isselected from hydrogen, methyl and ethyl. An embodiment of the presentinvention includes compounds wherein R³ is ethyl.

An embodiment of the present invention includes compounds wherein R⁵ isselected from the group consisting of:

-   -   (1) hydrogen,    -   (2) methyl,    -   (3) —C(CH₃)₂OH,    -   (4) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, and    -   (8) —C═O)OCH₃.

An embodiment of the present invention includes compounds wherein R⁵ isselected from the group consisting of: methyl and —C(CH₃)₂OH.

An embodiment of the present invention includes compounds wherein R⁶ isselected from the group consisting of:

-   -   (1) hydrogen,    -   (2) methyl,    -   (3) —C(CH₃)₂OH,    -   (4) —CH(OH)CF₃,    -   (5) —CH(OH)CH₃,    -   (6) —C(OH)(CH₃)CH₂CH₃,    -   (7) —C(OH)(CF₃)CH₃, and    -   (8) —C(═O)OCH₃.

An embodiment of the present invention includes compounds wherein R⁶ isselected from the group consisting of:

-   -   (1) hydrogen, and    -   (2) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen or hydroxyl.

An embodiment of the present invention includes compounds wherein R⁶ isselected from the group consisting of: methyl and —C(CH₃)₂OH.

An embodiment of the present invention includes compounds wherein R⁵ is—C(CH₃)₂OH and R⁶ is hydrogen or methyl. An embodiment of the presentinvention includes compounds wherein R⁵ is —C(CH₃)₂OH and R⁶ is methyl.An embodiment of the present invention includes compounds wherein R⁵ is—C(CH₃)₂OH and R⁶ is hydrogen. An embodiment of the present inventionincludes compounds wherein R⁵ is methyl and R⁶ is —C(CH₃)₂OH.

Certain embodiments of the present invention include a compound which isselected from the group consisting of the subject compounds of theExamples herein or a pharmaceutically acceptable salt thereof.

The compounds of the present invention may contain one or moreasymmetric centers and can thus occur as racemates and racemic mixtures,single enantiomers, diastereomeric mixtures and individualdiastereomers. Additional asymmetric centers may be present dependingupon the nature of the various substituents on the molecule. Each suchasymmetric center will independently produce two optical isomers and itis intended that all of the possible optical isomers and diastereomersin mixtures and as pure or partially purified compounds are includedwithin the ambit of this invention. The present invention is meant tocomprehend all such isomeric forms of these compounds. Formula I showsthe structure of the class of compounds without specificstereochemistry.

The independent syntheses of these diastereomers or theirchromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the x-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration. If desired, racemic mixtures ofthe compounds may be separated so that the individual enantiomers areisolated. The separation can be carried out by methods well known in theart, such as the coupling of a racemic mixture of compounds to anenantiomerically pure compound to form a diastereomeric mixture,followed by separation of the individual diastereomers by standardmethods, such as fractional crystallization or chromatography. Thecoupling reaction is often the formation of salts using anenantiomerically pure acid or base. The diasteromeric derivatives maythen be converted to the pure enantiomers by cleavage of the addedchiral residue. The racemic mixture of the compounds can also beseparated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

As appreciated by those of skill in the art, halogen or halo as usedherein are intended to include fluoro, chloro, bromo and iodo.Similarly, C₁₋₆, as in C₁₋₆alkyl is defined to identify the group ashaving 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement,such that C₁₋₆alkyl specifically includes methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, and hexyl. A groupwhich is designated as being independently substituted with substituentsmay be independently substituted with multiple numbers of suchsubstituents. The term “heteroaryl” as used herein includesbenzoimidazolyl, benzimidazolonyl, benzofuranyl, benzofurazanyl,benzopyrazolyl, benzothiazolyl, benzotriazolyl, benzothiophenyl,benzoxazepin, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl,imidazolyl, indolinyl, indolyl, dihydroindolyl, indolazinyl, indazolyl,isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl,naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline,oxetanyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl,pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl,quinoxalinyl, tetrahydroquinoxalinyl, tetrazolyl, tetrazolopyridyl,thiadiazolyl, thiazolyl, thienyl, triazolyl, and N-oxides thereof, andwherein the saturated heterocyclic moieties include azetidinyl,1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl,pyridin-2-onyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl,thiomorpholinyl, and tetrahydrothienyl, and N-oxides thereof.

The present invention also includes all pharmaceutically acceptableisotopic variations of a compound of the Formula I in which one or moreatoms is replaced by atoms having the same atomic number, but an atomicmass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes suitable for inclusion inthe compounds of the invention include isotopes of hydrogen such as ²Hand ³H, carbon such as ¹¹C, ¹³C and ¹⁴C, nitrogen such as ¹³N and ¹⁵N,oxygen such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus such as ³²P, sulfur such as³⁵S, fluorine such as ¹⁸F, iodine such as ¹²³I and ¹²⁵I, and chlorinesuch as ³⁶Cl. Certain isotopically-labelled compounds of Formula I, forexample those incorporating a radioactive isotope, are useful in drugand/or substrate tissue distribution studies. The radioactive isotopestritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful forthis purpose in view of their ease of incorporation and ready means ofdetection. Substitution with heavier isotopes such as deuterium, i.e.²H, may afford certain therapeutic advantages resulting from greatermetabolic stability, for example, increased in vivo half-life or reduceddosage requirements, and hence may be preferred in some circumstances.Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy. Isotopically-labelled compoundsof Formula I can generally be prepared by conventional techniques knownto those skilled in the art or by processes analogous to those describedin the accompanying Examples using appropriate isotopically-labelledreagents in place of the non-labelled reagent previously employed.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. Salts derivedfrom inorganic bases include aluminum, ammonium, calcium, copper,ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc, and the like. Particular embodiments includethe ammonium, calcium, magnesium, potassium, and sodium salts. Salts inthe solid form may exist in more than one crystal structure, and mayalso be in the form of hydrates. Salts derived from pharmaceuticallyacceptable organic non-toxic bases include salts of primary, secondary,and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, and basic ion exchange resins, suchas arginine, betaine, caffeine, choline, N,N′-dibenzylethylene-diamine,diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine,glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, andthe like. Particular embodiments include the citric, hydrobromic,hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids.It will be understood that, as used herein, references to the compoundsof Formula I are meant to also include the pharmaceutically acceptablesalts.

Exemplifying the invention is the use of the compounds disclosed in theExamples and herein. Specific compounds within the present inventioninclude a compound which is selected from the group consisting of thecompounds disclosed in the following Examples and pharmaceuticallyacceptable salts thereof and individual enantiomers or diastereomersthereof.

The present invention is also directed to the use of the compoundsdisclosed herein as antagonists of orexin receptor activity. The subjectcompounds and pharmaceutically acceptable salts thereof are useful in amethod of antagonizing orexin receptor activity in a subject such as amammal comprising the administration of an amount of the compound. Inaddition to primates, especially humans, a variety of other mammals maybe administered with a compound of the present invention. The presentinvention is directed to a compound of the present invention or apharmaceutically acceptable salt thereof that could be useful inthereapy. The present invention may further be directed to a use of acompound of the present invention or a pharmaceutically acceptable saltthereof for the manufacture of a medicament for antagonizing orexinreceptor activity or treating the disorders and diseases noted herein inhumans and animals.

A subject administered with a compound of the present invention, or apharmaceutically acceptable salt thereof, is generally a mammal, such asa human being, male or female. The amount of compound administered tothe subject is an amount sufficient to antagonize the orexin receptor inthe subject. In an embodiment, the amount of compound can be an“effective amount”, wherein the subject compound is administered in anamount that will elicit the biological or medical response of a tissue,system, animal or human that is being sought by the researcher,veterinarian, medical doctor or other clinician. An effective amountdoes not necessarily include considerations of toxicity and safetyrelated to the administration of the compound. It is recognized that oneskilled in the art may affect neurological and psychiatric disordersassociated with orexin receptor activation by treating a subjectpresently afflicted with the disorders, or by prophylactically treatinga subject likely to be afflicted with the disorders, with an effectiveamount of a compound of the present invention. As used herein, the terms“treatment” and “treating” refer to all processes wherein there may be aslowing, interrupting, arresting, controlling, or stopping of theprogression of the neurological and psychiatric disorders describedherein, but does not necessarily indicate a total elimination of alldisorder symptoms, as well as the prophylactic therapy of the mentionedconditions, particularly in a subject that is predisposed to suchdisease or disorder. The terms “administration of” and or “administeringa” compound should be understood to mean providing a compound of theinvention or a prodrug of a compound of the invention to the subject.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term isintended to encompass a product comprising the active ingredient(s), andthe inert ingredient(s) that make up the carrier, as well as any productwhich results, directly or indirectly, from combination, complexation oraggregation of any two or more of the ingredients, or from dissociationof one or more of the ingredients, or from other types of reactions orinteractions of one or more of the ingredients. Accordingly, thecompositions of the present invention encompass any composition made byadmixing a compound of the present invention and a pharmaceuticallyacceptable carrier. By “pharmaceutically acceptable” it is meant thecarrier, diluent or excipient must be compatible with the otheringredients of the formulation and not deleterious to the recipientthereof.

The utility of the compounds in accordance with the present invention asorexin receptor OX1R and/or OX2R antagonists may be readily determinedwithout undue experimentation by methodology well known in the art,including the “FLIPR Ca²⁺ Flux Assay” (Okumura et al., Biochem. Biophys.Res. Comm. 280:976-981, 2001). In a typical experiment the OX1 and OX2receptor antagonistic activity of the compounds of the present inventionwas determined in accordance with the following experimental method. Forintracellular calcium measurements, Chinese hamster ovary (CHO) cellsexpressing the rat orexin-1 receptor or the human orexin-2 receptor, aregrown in Iscove's modified DMEM containing 2 mM L-glutamine, 0.5 g/mlG418, 1% hypoxanthine-thymidine supplement, 100 U/ml penicillin, 100μg/ml streptomycin and 10% heat-inactivated fetal calf serum (FCS). Thecells are seeded at 20,000 cells/well into Becton-Dickinson black384-well clear bottom sterile plates coated with poly-D-lysine. Allreagents were from GIBCO-Invitrogen Corp. The seeded plates areincubated overnight at 37° C. and 5% CO2. Ala-6,12 human orexin-A as theagonist is prepared as a 1 mM stock solution in 1% bovine serum albumin(BSA) and diluted in assay buffer (HBSS containing 20 mM HEPES, 0.1% BSAand 2.5 mM probenecid, pH7.4) for use in the assay at a finalconcentration of 70 pM. Test compounds are prepared as 10 mM stocksolution in DMSO, then diluted in 384-well plates, first in DMSO, thenassay buffer. On the day of the assay, cells are washed 3 times with 100μl assay buffer and then incubated for 60 min (37° C., 5% CO2) in 60 μlassay buffer containing 1 μM Fluo-4AM ester, 0.02% pluronic acid, and 1%BSA. The dye loading solution is then aspirated and cells are washed 3times with 100 μl assay buffer. 30 μl of that same buffer is left ineach well. Within the Fluorescent Imaging Plate Reader (FLIPR, MolecularDevices), test compounds are added to the plate in a volume of 25 μl,incubated for 5 min and finally 25 μl of agonist is added. Fluorescenceis measured for each well at 1 second intervals for 5 minutes and theheight of each fluorescence peak is compared to the height of thefluorescence peak induced by 70 pM Ala-6,12 orexin-A with buffer inplace of antagonist. For each antagonist, IC50 value (the concentrationof compound needed to inhibit 50% of the agonist response) isdetermined. Alternatively, compound potency can be assessed by aradioligand binding assay (described in Bergman et. al. Bioorg. Med.Chem. Lett. 2008, 18, 1425-1430) in which the inhibition constant(K_(i)) is determined in membranes prepared from CHO cells expressingeither the OX1 or OX2 receptor. The intrinsic orexin receptor antagonistactivity of a compound which may be used in the present invention may bedetermined by these assays.

All of the final compounds of the following examples had activity inantagonizing the human orexin-2 receptor in the aforementioned assayswith an IC50 of about 0.1 nM to 1500 nM. All of the final compounds ofthe following examples had activity in the FLIPR assay with an IC50 ofabout 5 nM to 500 nM against the orexin-2 receptor. Additional data isprovided in the following Examples. Such a result is indicative of theintrinsic activity of the compounds in use as antagonists of orexin-1receptor and/or the orexin-2 receptor. In general, one of ordinary skillin the art would appreciate that a substance is considered toeffectively antagonize the orexin receptor if it has an IC50 of lessthan about 50 μM, or more specifically less than about 1000 nM.

The orexin receptors have been implicated in a wide range of biologicalfunctions. This has suggested a potential role for these receptors in avariety of disease processes in humans or other species. The compoundsof the present invention could therefore potentially have utility intreating, preventing, ameliorating, controlling or reducing the risk ofa variety of neurological and psychiatric disorders associated withorexin receptors, including one or more of the following conditions ordiseases: sleep disorders, sleep disturbances, including enhancing sleepquality, improving sleep quality, increasing sleep efficiency,augmenting sleep maintenance; increasing the value which is calculatedfrom the time that a subject sleeps divided by the time that a subjectis attempting to sleep; improving sleep initiation; decreasing sleeplatency or onset (the time it takes to fall asleep); decreasingdifficulties in falling asleep; increasing sleep continuity; decreasingthe number of awakenings during sleep; decreasing intermittent wakingsduring sleep; decreasing nocturnal arousals; decreasing the time spentawake following the initial onset of sleep; increasing the total amountof sleep; reducing the fragmentation of sleep; altering the timing,frequency or duration of REM sleep bouts; altering the timing, frequencyor duration of slow wave (i.e. stages 3 or 4) sleep bouts; increasingthe amount and percentage of stage 2 sleep; promoting slow wave sleep;enhancing EEG-delta activity during sleep; decreasing nocturnalarousals, especially early morning awakenings; increasing daytimealertness; reducing daytime drowsiness; treating or reducing excessivedaytime sleepiness; increasing satisfaction with the intensity of sleep;increasing sleep maintenance; idiopathic insomnia; sleep problems;insomnia, hypersomnia, idiopathic hypersomnia, repeatabilityhypersomnia, intrinsic hypersomnia, narcolepsy, interrupted sleep, sleepapnea, wakefulness, nocturnal myoclonus, REM sleep interruptions,jet-lag, shift workers' sleep disturbances, dyssomnias, night terror,insomnias associated with depression, emotional/mood disorders,Alzheimer's disease or cognitive impairment, as well as sleep walkingand enuresis, and sleep disorders which accompany aging; Alzheimer'ssundowning; conditions associated with circadian rhythmicity as well asmental and physical disorders associated with travel across time zonesand with rotating shift-work schedules, conditions due to drugs whichcause reductions in REM sleep as a side effect; fibromyalgia; syndromeswhich are manifested by non-restorative sleep and muscle pain or sleepapnea which is associated with respiratory disturbances during sleep;conditions which result from a diminished quality of sleep; increasinglearning; augmenting memory; increasing retention of memory; eatingdisorders associated with excessive food intake and complicationsassociated therewith, compulsive eating disorders, obesity (due to anycause, whether genetic or environmental), obesity-related disordersovereating, anorexia, bulimia, cachexia, dysregulated appetite control,hypertension, diabetes, elevated plasma insulin concentrations andinsulin resistance, dyslipidemias, hyperlipidemia, endometrial, breast,prostate and colon cancer, osteoarthritis, obstructive sleep apnea,cholelithiasis, gallstones, heart disease, lung disease, abnormal heartrhythms and arrythmias, myocardial infarction, congestive heart failure,coronary heart disease, acute and congestive heart failure; hypotension;hypertension; urinary retention; osteoporosis; angina pectoris;myocardinal infarction; ischemic or haemorrhagic stroke; subarachnoidhaemorrhage; ulcers; allergies; benign prostatic hypertrophy; chronicrenal failure; renal disease; impaired glucose tolerance; sudden death,polycystic ovary disease, craniopharyngioma, the Prader-Willi Syndrome,Frohlich's syndrome, GH-deficient subjects, normal variant shortstature, Turner's syndrome, and other pathological conditions showingreduced metabolic activity or a decrease in resting energy expenditureas a percentage of total fat-free mass, e.g, children with acutelymphoblastic leukemia, metabolic syndrome, also known as syndrome X,insulin resistance syndrome, reproductive hormone abnormalities, sexualand reproductive dysfunction, such as impaired fertility, infertility,hypogonadism in males and hirsutism in females, fetal defects associatedwith maternal obesity, gastrointestinal motility disorders, intestinalmotility dyskinesias, obesity-related gastro-esophageal reflux,hypothalmic diseases, hypophysis diseases, respiratory disorders, suchas obesity-hypoventilation syndrome (Pickwickian syndrome),breathlessness, cardiovascular disorders, inflammation, such as systemicinflammation of the vasculature, arteriosclerosis, hypercholesterolemia,hyperuricaemia, lower back pain, gallbladder disease, gout, kidneycancer, increased anesthetic risk, reducing the risk of secondaryoutcomes of obesity, such as reducing the risk of left ventricularhypertrophy; diseases or disorders where abnormal oscillatory activityoccurs in the brain, including depression, migraine, neuropathic pain,Parkinson's disease, psychosis and schizophrenia, as well as diseases ordisorders where there is abnormal coupling of activity, particularlythrough the thalamus; enhancing cognitive function, including cognitivedysfunctions that comprise deficits in all types of attention, learningand memory functions occurring transiently or chronically in the normal,healthy, young, adult or aging population, and also occurringtransiently or chronically in psychiatric, neurologic, cardiovascularand immune disorders; enhancing memory; increasing memory retention;increasing immune response; increasing immune function; hot flashes;night sweats; extending life span; schizophrenia; muscle-relateddisorders that are controlled by the excitation/relaxation rhythmsimposed by the neural system such as cardiac rhythm and other disordersof the cardiovascular system; conditions related to proliferation ofcells such as vasodilation or vasorestriction and blood pressure;cancer; cardiac arrhythmia; hypertension; congestive heart failure;conditions of the genital/urinary system; disorders of sexual functionand fertility; adequacy of renal function; responsivity to anesthetics;mood disorders, such as depression or more particularly depressivedisorders, for example, single episodic or recurrent major depressivedisorders and dysthymic disorders, or bipolar disorders, for example,bipolar I disorder, bipolar II disorder and cyclothymic disorder, mooddisorders due to a general medical condition, and substance-induced mooddisorders; affective neurosis; depressive neurosis; anxiety neurosis;anxiety disorders including acute stress disorder, agoraphobia,generalized anxiety disorder, obsessive-compulsive disorder, panicattack, panic disorder, post-traumatic stress disorder, separationanxiety disorder, social phobia, specific phobia, substance-inducedanxiety disorder and anxiety due to a general medical condition; acuteneurological and psychiatric disorders such as cerebral deficitssubsequent to cardiac bypass surgery and grafting, stroke, ischemicstroke, cerebral ischemia, spinal cord trauma, head trauma, perinatalhypoxia, cardiac arrest, hypoglycemic neuronal damage; Huntington'sChorea; Huntington's disease and Tourette syndrome; Cushing'ssyndrome/disease; basophile adenoma; prolactinoma; hyperprolactinemia;hypophysis tumor/adenoma; hypothalamic diseases; inflammatory boweldisease; gastric diskinesia; gastric ulcers; Froehlich's syndrome;adrenohypophysis disease; hypophysis disease; adrenohypophysishypofunction; adrenohypophysis hyperfunction; hypothalamic hypogonadism;Kallman's syndrome (anosmia, hyposmia); functional or psychogenicamenorrhea; hypopituitarism; hypothalamic hypothyroidism;hypothalamic-adrenal dysfunction; idiopathic hyperprolactinemia;hypothalamic disorders of growth hormone deficiency; idiopathic growthdeficiency; dwarfism; gigantism; acromegaly; amyotrophic lateralsclerosis; multiple sclerosis; ocular damage; retinopathy; cognitivedisorders; idiopathic and drug-induced Parkinson's disease; muscularspasms and disorders associated with muscular spasticity includingtremors, epilepsy, convulsions, seizure disorders, absence seisures,complex partial and generalized seizures; Lennox-Gastaut syndrome;cognitive disorders including dementia (associated with Alzheimer'sdisease, ischemia, trauma, vascular problems or stroke, HIV disease,Parkinson's disease, Huntington's disease, Pick's disease,Creutzfeldt-Jacob disease, perinatal hypoxia, other general medicalconditions or substance abuse); delirium, amnestic disorders or agerelated cognitive decline; schizophrenia or psychosis includingschizophrenia (paranoid, disorganized, catatonic or undifferentiated),schizophreniform disorder, schizoaffective disorder, delusionaldisorder, brief psychotic disorder, shared psychotic disorder, psychoticdisorder due to a general medical condition and substance-inducedpsychotic disorder; dissociative disorders including multiplepersonality syndromes and psychogenic amnesias; substance-relateddisorders, substance use, substance abuse, substance seeking, substancereinstatement, all types of psychological and physical addictions andaddictive behaviors, reward-related behaviors (includingsubstance-induced delirium, persisting dementia, persisting amnesticdisorder, psychotic disorder or anxiety disorder; tolerance, addictivefeeding, addictive feeding behaviors, binge/purge feeding behaviors,dependence, withdrawal or relapse from substances including alcohol,amphetamines, cannabis, cocaine, hallucinogens, inhalants, morphine,nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics);appetite, taste, eating or drinking disorders; movement disorders,including akinesias and akinetic-rigid syndromes (including Parkinson'sdisease, drug-induced parkinsonism, postencephalitic parkinsonism,progressive supranuclear palsy, multiple system atrophy, corticobasaldegeneration, parkinsonism-ALS dementia complex and basal gangliacalcification), chronic fatigue syndrome, fatigue, including Parkinson'sfatigue, multiple sclerosis fatigue, fatigue caused by a sleep disorderor a circadian rhythm disorder, medication-induced parkinsonism (such asneuroleptic-induced parkinsonism, neuroleptic malignant syndrome,neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia,neuroleptic-induced tardive dyskinesia and medication-induced posturaltremor), Gilles de la Tourette's syndrome, epilepsy, and dyskinesias[including tremor (such as rest tremor, essential tremor, posturaltremor and intention tremor), chorea (such as Sydenham's chorea,Huntington's disease, benign hereditary chorea, neuroacanthocytosis,symptomatic chorea, drug-induced chorea and hemiballism), myoclonus(including generalised myoclonus and focal myoclonus), tics (includingsimple tics, complex tics and symptomatic tics), restless leg syndromeand dystonia (including generalised dystonia such as iodiopathicdystonia, drug-induced dystonia, symptomatic dystonia and paroxymaldystonia, and focal dystonia such as blepharospasm, oromandibulardystonia, spasmodic dysphonia, spasmodic torticollis, axial dystonia,dystonic writer's cramp and hemiplegic dystonia); neurodegenerativedisorders including nosological entities such asdisinhibition-dementia-parkinsonism-amyotrophy complex;pallido-ponto-nigral degeneration; epilepsy; seizure disorders;attention deficit/hyperactivity disorder (ADHD); conduct disorder;migraine (including migraine headache); headache; hyperalgesia; pain;enhanced or exaggerated sensitivity to pain such as hyperalgesia,causalgia, and allodynia; acute pain; burn pain; atypical facial pain;neuropathic pain; back pain; complex regional pain syndrome I and II;arthritic pain; sports injury pain; pain related to infection e.g. HIV,post-chemotherapy pain; post-stroke pain; post-operative pain;neuralgia; emesis, nausea, vomiting; gastric dyskinesia; gastric ulcers;Kallman's syndrome (anosmia); asthma; cancer; conditions associated withvisceral pain such as irritable bowel syndrome, and angina; eatingdisorders; urinary incontinence; substance tolerance, substancewithdrawal (including, substances such as opiates, nicotine, tobaccoproducts, alcohol, benzodiazepines, cocaine, sedatives, hypnotics,etc.); psychosis; schizophrenia; anxiety (including generalized anxietydisorder, panic disorder, and obsessive compulsive disorder); mooddisorders (including depression, mania, bipolar disorders); trigeminalneuralgia; hearing loss; tinnitus; neuronal damage including oculardamage; retinopathy; macular degeneration of the eye; emesis; brainedema; pain, including acute and chronic pain states, severe pain,intractable pain, inflammatory pain, neuropathic pain, post-traumaticpain, bone and joint pain (osteoarthritis), repetitive motion pain,dental pain, cancer pain, myofascial pain (muscular injury,fibromyalgia), perioperative pain (general surgery, gynecological),chronic pain, neuropathic pain, post-traumatic pain, trigeminalneuralgia, migraine and migraine headache and other diseases related togeneral orexin system dysfunction.

Thus, in certain embodiments the present invention may provide methodsfor: enhancing the quality of sleep; augmenting sleep maintenance;increasing REM sleep; increasing stage 2 sleep; decreasing fragmentationof sleep patterns; treating insomnia and all types of sleep disorders;treating or controlling sleep disturbances associated with diseases suchas neurological disorders including neuropathic pain and restless legsyndrome; treating or controlling addiction disorders; treating orcontrolling psychoactive substance use and abuse; enhancing cognition;increasing memory retention; treating or controlling obesity; treatingor controlling diabetes and appetite, taste, eating, or drinkingdisorders; treating or controlling hypothalamic diseases; treating orcontrolling depression; treating, controlling, ameliorating or reducingthe risk of epilepsy, including absence epilepsy; treating orcontrolling pain, including neuropathic pain; treating or controllingParkinson's disease; treating or controlling psychosis; treating orcontrolling dysthymic, mood, psychotic and anxiety disorders; treatingor controlling depression, including major depression and majordepression disorder; treating or controlling bipolar disorder; ortreating, controlling, ameliorating or reducing the risk ofschizophrenia, in a mammalian subject which comprises administering tothe subject a compound of the present invention.

The subject compounds could further be of potential use in a method forthe prevention, treatment, control, amelioration, or reduction of riskof the diseases, disorders and conditions noted herein. The dosage ofactive ingredient in the compositions of this invention may be varied,however, it is necessary that the amount of the active ingredient besuch that a suitable dosage form is obtained. The active ingredient maybe administered to subjects (animals and human) in need of suchtreatment in dosages that will provide optimal pharmaceutical efficacy.The selected dosage depends upon the desired therapeutic effect, on theroute of administration, and on the duration of the treatment. The dosewill vary from subject to subject depending upon the nature and severityof disease, the subject's weight, special diets then being followed by asubject, concurrent medication, and other factors which those skilled inthe art will recognize. Generally, dosage levels of between 0.0001 to 10mg/kg. of body weight daily are administered to the subject, e.g.,humans and elderly humans, to obtain effective antagonism of orexinreceptors. The dosage range will generally be about 0.5 mg to 1.0 g. persubject per day which may be administered in single or multiple doses.In one embodiment, the dosage range will be about 0.5 mg to 500 mg persubject per day; in another embodiment about 0.5 mg to 200 mg persubject per day; and in yet another embodiment about 5 mg to 50 mg persubject per day. Pharmaceutical compositions of the present inventionmay be provided in a solid dosage formulation such as comprising about0.5 mg to 500 mg active ingredient, or comprising about 1 mg to 250 mgactive ingredient. The pharmaceutical composition may be provided in asolid dosage formulation comprising about 1 mg, 5 mg, 10 mg, 25 mg, 30mg, 50 mg, 80 mg, 100 mg, 200 mg or 250 mg active ingredient. For oraladministration, the compositions may be provided in the form of tabletscontaining 1.0 to 1000 milligrams of the active ingredient, such as 1,5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750,800, 900, and 1000 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the subject to be treated. Thecompounds may be administered on a regimen of 1 to 4 times per day, suchas once or twice per day. The compounds may be administered beforebedtime. For example, the compounds may be administered about 1 Hourprior to bedtime, about 30 minutes prior to bedtime or immediatelybefore bedtime.

The compounds of the present invention may be used in combination withone or more other drugs in the treatment, prevention, control,amelioration, or reduction of risk of diseases or conditions for whichcompounds of the present invention or the other drugs may have utility,where the combination of the drugs together are safer or more effectivethan either drug alone. Such other drug(s) may be administered, by aroute and in an amount commonly used therefor, contemporaneously orsequentially with a compound of the present invention. When a compoundof the present invention is used contemporaneously with one or moreother drugs, a pharmaceutical composition in unit dosage form containingsuch other drugs and the compound of the present invention iscontemplated. However, the combination therapy may also includetherapies in which the compound of the present invention and one or moreother drugs are administered on different overlapping schedules. It isalso contemplated that when used in combination with one or more otheractive ingredients, the compounds of the present invention and the otheractive ingredients may be used in lower doses than when each is usedsingly. Accordingly, the pharmaceutical compositions of the presentinvention include those that contain one or more other activeingredients, in addition to a compound of the present invention. Theabove combinations include combinations of a compound of the presentinvention not only with one other active compound, but also with two ormore other active compounds.

Likewise, compounds of the present invention may be used in combinationwith other drugs that are used in the prevention, treatment, control,amelioration, or reduction of risk of the diseases or conditions forwhich compounds of the present invention are useful. Such other drugsmay be administered, by a route and in an amount commonly used therefor,contemporaneously or sequentially with a compound of the presentinvention. When a compound of the present invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofthe present invention is contemplated. Accordingly, the pharmaceuticalcompositions of the present invention include those that also containone or more other active ingredients, in addition to a compound of thepresent invention.

The weight ratio of the compound of the present invention to the secondactive ingredient may be varied and will depend upon the effective doseof each ingredient. Generally, an effective dose of each will be used.Thus, for example, when a compound of the present invention is combinedwith another agent, the weight ratio of the compound of the presentinvention to the other agent will generally range from about 1000:1 toabout 1:1000, such as about 200:1 to about 1:200. Combinations of acompound of the present invention and other active ingredients willgenerally also be within the aforementioned range, but in each case, aneffective dose of each active ingredient should be used. In suchcombinations the compound of the present invention and other activeagents may be administered separately or in conjunction. In addition,the administration of one element may be prior to, concurrent to, orsubsequent to the administration of other agent(s).

The compounds of the present invention may be administered incombination with other compounds which are known in the art to be usefulfor enhancing sleep quality and preventing and treating sleep disordersand sleep disturbances, including e.g., sedatives, hypnotics,anxiolytics, antipsychotics, antianxiety agents, antihistamines,benzodiazepines, barbiturates, cyclopyrrolones, GABA agonists, 5HT-2antagonists including 5HT-2A antagonists and 5HT-2A/2C antagonists,histamine antagonists including histamine H3 antagonists, histamine H3inverse agonists, imidazopyridines, minor tranquilizers, melatoninagonists and antagonists, melatonergic agents, other orexin antagonists,orexin agonists, prokineticin agonists and antagonists,pyrazolopyrimidines, T-type calcium channel antagonists,triazolopyridines, and the like, such as: adinazolam, allobarbital,alonimid, alprazolam, amitriptyline, amobarbital, amoxapine,armodafinil, APD-125, bentazepam, benzoctamine, brotizolam, bupropion,busprione, butabarbital, butalbital, capromorelin, capuride,carbocloral, chloral betaine, chloral hydrate, chlordiazepoxide,clomipramine, clonazepam, cloperidone, clorazepate, clorethate,clozapine, conazepam, cyprazepam, desipramine, dexclamol, diazepam,dichloralphenazone, divalproex, diphenhydramine, doxepin, EMD-281014,eplivanserin, estazolam, eszopiclone, ethchlorynol, etomidate, fenobam,flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam,gaboxadol, glutethimide, halazepam, hydroxyzine, ibutamoren, imipramine,indiplon, lithium, lorazepam, lormetazepam, LY-156735, maprotiline,MDL-100907, mecloqualone, melatonin, mephobarbital, meprobamate,methaqualone, methyprylon, midaflur, midazolam, modafinil, nefazodone,NGD-2-73, nisobamate, nitrazepam, nortriptyline, omortriptyline,oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine,perphenazine, phenelzine, phenobarbital, prazepam, promethazine,propofol, protriptyline, quazepam, ramelteon, reclazepam, roletamide,secobarbital, sertraline, suproclone, TAK-375, temazepam, thioridazine,tiagabine, tracazolate, tranylcypromaine, trazodone, triazolam,trepipam, tricetamide, triclofos, trifluoperazine, trimetozine,trimipramine, uldazepam, venlafaxine, zaleplon, zolazepam, zopiclone,zolpidem, and salts thereof, and combinations thereof, and the like, orthe compound of the present invention may be administered in conjunctionwith the use of physical methods such as with light therapy orelectrical stimulation.

In another embodiment, the subject compound may be employed incombination with other compounds which are known in the art, eitheradministered separately or in the same pharmaceutical compositions,including, but are not limited to: insulin sensitizers including (i)PPARγ antagonists such as glitazones (e.g. ciglitazone; darglitazone;englitazone; isaglitazone (MCC-555); pioglitazone; rosiglitazone;troglitazone; tularik; BRL49653; CLX-0921; 5-BTZD), GW-0207, LG-100641,and LY-300512, and the like); (iii) biguanides such as metformin andphenformin; (b) insulin or insulin mimetics, such as biota, LP-100,novarapid, insulin detemir, insulin lispro, insulin glargine, insulinzinc suspension (lente and ultralente); Lys-Pro insulin, GLP-1 (73-7)(insulintropin); and GLP-1 (7-36)-NH₂); (c) sulfonylureas, such asacetohexamide; chlorpropamide; diabinese; glibenclamide; glipizide;glyburide; glimepiride; gliclazide; glipentide; gliquidone; glisolamide;tolazamide; and tolbutamide; (d) α-glucosidase inhibitors, such asacarbose, adiposine; camiglibose; emiglitate; miglitol; voglibose;pradimicin-Q; salbostatin; CKD-711; MDL-25,637; MDL-73,945; and MOR 14,and the like; (e) cholesterol lowering agents such as (i) HMG-CoAreductase inhibitors (atorvastatin, itavastatin, fluvastatin,lovastatin, pravastatin, rivastatin, rosuvastatin, simvastatin, andother statins), (ii) bile acid absorbers/sequestrants, such ascholestyramine, colestipol, dialkylaminoalkyl derivatives of across-linked dextran; Colestid®; LoCholest®, and the like, (ii)nicotinyl alcohol, nicotinic acid or a salt thereof, (iii)proliferator-activater receptor a agonists such as fenofibric acidderivatives (gemfibrozil, clofibrate, fenofibrate and benzafibrate),(iv) inhibitors of cholesterol absorption such as stanol esters,beta-sitosterol, sterol glycosides such as tiqueside; and azetidinonessuch as ezetimibe, and the like, and (acyl CoA:cholesterolacyltransferase (ACAT)) inhibitors such as avasimibe, and melinamide,(v) anti-oxidants, such as probucol, (vi) vitamin E, and (vii)thyromimetics; (f) PPARα agonists such as beclofibrate, benzafibrate,ciprofibrate, clofibrate, etofibrate, fenofibrate, and gemfibrozil; andother fibric acid derivatives, such as Atromid®, Lopid® and Tricor®, andthe like, and PPARα agonists as described in WO 97/36579; (g) PPARδagonists, such as those disclosed in WO97/28149; (h) PPAR α/δ agonists,such as muraglitazar, and the compounds disclosed in U.S. Pat. No.6,414,002; (i) anti-obesity agents, such as (1) growth hormonesecretagogues, growth hormone secretagogue receptoragonists/antagonists, such as NN703, hexarelin, MK-0677, SM-130686,CP-424,391, L-692,429, and L-163,255, and such as those disclosed inU.S. Pat. Nos. 5,536,716, and 6,358,951, U.S. Patent Application Nos.2002/049196 and 2002/022637, and PCT Application Nos. WO 01/56592 and WO02/32888; (2) protein tyrosine phosphatase-1B (PTP-1B) inhibitors; (3)cannabinoid receptor ligands, such as cannabinoid CB₁ receptorantagonists or inverse agonists, such as rimonabant, taranabant,AMT-251, and SR-14778 and SR 141716A (Sanofi Synthelabo), SLV-319(Solvay), BAY 65-2520 (Bayer) and those disclosed in U.S. Pat. Nos.5,532,237, 4,973,587, 5,013,837, 5,081,122, 5,112,820, 5,292,736,5,624,941, 6,028,084, PCT Application Nos. WO 96/33159, WO 98/33765,WO98/43636, WO98/43635, WO 01/09120, WO98/31227, WO98/41519, WO98/37061,WO00/10967, WO00/10968, WO97/29079, WO99/02499, WO 01/58869, WO01/64632, WO 01/64633, WO 01/64634, WO02/076949, WO 03/007887, WO04/048317, and WO 05/000809; (4) anti-obesity serotonergic agents, suchas fenfluramine, dexfenfluramine, phentermine, and sibutramine; (5)β3-adrenoreceptor agonists, such as AD9677/TAK677 (Dainippon/Takeda),CL-316,243, SB 418790, BRL-37344, L-796568, BMS-196085, BRL-35135A,CGP12177A, BTA-243, Trecadrine, Zeneca D7114, SR 59119A; (6) pancreaticlipase inhibitors, such as orlistat (Xenical®), Triton WR1339, RHC80267,lipstatin, tetrahydrolipstatin, teasaponin, diethylumbelliferylphosphate, and those disclosed in PCT Application No. WO 01/77094; (7)neuropeptide Y1 antagonists, such as BIBP3226, J-115814, BIBO 3304,LY-357897, CP-671906, GI-264879A, and those disclosed in U.S. Pat. No.6,001,836, and PCT Patent Publication Nos. WO 96/14307, WO 01/23387, WO99/51600, WO 01/85690, WO 01/85098, WO 01/85173, and WO 01/89528; (8)neuropeptide Y5 antagonists, such as GW-569180A, GW-594884A, GW-587081X,GW-548118X, FR226928, FR 240662, FR252384, 1229U91, GI-264879A,CGP71683A, LY-377897, PD-160170, SR-120562A, SR-120819A and JCF-104, andthose disclosed in U.S. Pat. Nos. 6,057,335; 6,043,246; 6,140,354;6,166,038; 6,180,653; 6,191,160; 6,313,298; 6,335,345; 6,337,332;6,326,375; 6,329,395; 6,340,683; 6,388,077; 6,462,053; 6,649,624; and6,723,847, European Patent Nos. EP-01010691, and EP-01044970; and PCTInternational Patent Publication Nos. WO 97/19682, WO 97/20820, WO97/20821, WO 97/20822, WO 97/20823, WO 98/24768; WO 98/25907; WO98/25908; WO 98/27063, WO 98/47505; WO 98/40356; WO 99/15516; WO99/27965; WO 00/64880, WO 00/68197, WO 00/69849, WO 01/09120, WO01/14376; WO 01/85714, WO 01/85730, WO 01/07409, WO 01/02379, WO01/02379, WO 01/23388, WO 01/23389, WO 01/44201, WO 01/62737, WO01/62738, WO 01/09120, WO 02/22592, WO 0248152, and WO 02/49648; WO02/094825; WO 03/014083; WO 03/10191; WO 03/092889; WO 04/002986; and WO04/031175; (9) melanin-concentrating hormone (MCH) receptor antagonists,such as those disclosed in WO 01/21577 and WO 01/21169; (10)melanin-concentrating hormone 1 receptor (MCH1R) antagonists, such asT-226296 (Takeda), and those disclosed in PCT Patent Application Nos. WO01/82925, WO 01/87834, WO 02/051809, WO 02/06245, WO 02/076929, WO02/076947, WO 02/04433, WO 02/51809, WO 02/083134, WO 02/094799, WO03/004027; (11) melanin-concentrating hormone 2 receptor (MCH2R)agonist/antagonists; (12) orexin receptor antagonists, such asSB-334867-A, and those disclosed in patent publications herein; (13)serotonin reuptake inhibitors such as fluoxetine, paroxetine, andsertraline; (14) melanocortin agonists, such as Melanotan II; (15) Mc4r(melanocortin 4 receptor) agonists, such as CHIR86036 (Chiron),ME-10142, and ME-10145 (Melacure), CHIR86036 (Chiron); PT-141, and PT-14(Palatin); (16) 5HT-2 agonists; (17) 5HT2C (serotonin receptor 2C)agonists, such as BVT933, DPCA37215, WAY161503, R-1065, and thosedisclosed in U.S. Pat. No. 3,914,250, and PCT Application Nos. WO02/36596, WO 02/48124, WO 02/10169, WO 01/66548, WO 02/44152, WO02/51844, WO 02/40456, and WO 02/40457; (18) galanin antagonists; (19)CCK agonists; (20) CCK-A (cholecystokinin-A) agonists, such as AR-R15849, GI 181771, JMV-180, A-71378, A-71623 and SR14613, and thosedescribed in U.S. Pat. No. 5,739,106; (21) GLP-1 agonists; (22)corticotropin-releasing hormone agonists; (23) histamine receptor-3 (H3)modulators; (24) histamine receptor-3 (H3) antagonists/inverse agonists,such as hioperamide, 3-(1H-imidazol-4-yl)propyl N-(4-pentenyl)carbamate,clobenpropit, iodophenpropit, imoproxifan, GT2394 (Gliatech), andO-[3-(1H-imidazol-4-yl)propanol]-carbamates; (25) β-hydroxy steroiddehydrogenase-1 inhibitors (β-HSD-1); (26) PDE (phosphodiesterase)inhibitors, such as theophylline, pentoxifylline, zaprinast, sildenafil,amrinone, milrinone, cilostamide, rolipram, and cilomilast; (27)phosphodiesterase-3B (PDE3B) inhibitors; (28) NE (norepinephrine)transport inhibitors, such as GW 320659, despiramine, talsupram, andnomifensine; (29) ghrelin receptor antagonists, such as those disclosedin PCT Application Nos. WO 01/87335, and WO 02/08250; (30) leptin,including recombinant human leptin (PEG-OB, Hoffman La Roche) andrecombinant methionyl human leptin (Amgen); (31) leptin derivatives;(32) BRS3 (bombesin receptor subtype 3) agonists such as[D-Phe6,beta-Ala11,Phe13,Nle14]Bn(6-14) and[D-Phe6,Phe13]Bn(6-13)propylamide, and those compounds disclosed inPept. Sci. 2002 August; 8(8): 461-75); (33) CNTF (Ciliary neurotrophicfactors), such as GI-181771 (Glaxo-SmithKline), SR146131 (SanofiSynthelabo), butabindide, PD170,292, and PD 149164 (Pfizer); (34) CNTFderivatives, such as axokine (Regeneron); (35) monoamine reuptakeinhibitors, such as sibutramine; (36) UCP-1 (uncoupling protein-1), 2,or 3 activators, such as phytanic acid,4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl)-1-propenyl]benzoicacid (TTNPB), retinoic acid; (37) thyroid hormone β agonists, such asKB-2611 (KaroBioBMS); (38) FAS (fatty acid synthase) inhibitors, such asCerulenin and C75; (39) DGAT1 (diacylglycerol acyltransferase 1)inhibitors; (40) DGAT2 (diacylglycerol acyltransferase 2) inhibitors;(41) ACC2 (acetyl-CoA carboxylase-2) inhibitors; (42) glucocorticoidantagonists; (43) acyl-estrogens, such as oleoyl-estrone, disclosed indel Mar-Grasa, M. et al., Obesity Research, 9:202-9 (2001); (44)dipeptidyl peptidase IV (DP-IV) inhibitors, such as isoleucinethiazolidide, valine pyrrolidide, NVP-DPP728, LAF237, P93/01, TSL 225,TMC-2A/2B/2C, FE 999011, P9310/K364, VIP 0177, SDZ 274-444, sitagliptin;and the compounds disclosed in U.S. Pat. No. 6,699,871, WO 03/004498; WO03/004496; EP 1 258 476; WO 02/083128; WO 02/062764; WO 03/000250; WO03/002530; WO 03/002531; WO 03/002553; WO 03/002593; WO 03/000180; andWO 03/000181; (46) dicarboxylate transporter inhibitors; (47) glucosetransporter inhibitors; (48) phosphate transporter inhibitors; (49)Metformin (Glucophage®); (50) Topiramate (Topimax®); (50) peptide YY,PYY 3-36, peptide YY analogs, derivatives, and fragments such asBIM-43073D, BIM-43004C (Olitvak, D. A. et al., Dig. Dis. Sci.44(3):643-48 (1999)); (51) Neuropeptide Y2 (NPY2) receptor agonists suchNPY3-36, N acetyl [Leu(28,31)] NPY 24-36, TASP-V, andcyclo-(28/32)-Ac-[Lys28-Glu32]-(25-36)-pNPY; (52) Neuropeptide Y4 (NPY4)agonists such as pancreatic peptide (PP), and other Y4 agonists such as1229U91; (54) cyclooxygenase-2 inhibitors such as etoricoxib, celecoxib,valdecoxib, parecoxib, lumiracoxib, BMS347070, tiracoxib or JTE522,ABT963, CS502 and GW406381; (55) Neuropeptide Y1 (NPY1) antagonists suchas BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906, GI-264879A; (56)Opioid antagonists such as nalmefene (Revex®), 3-methoxynaltrexone,naloxone, naltrexone; (57) 11β HSD-1 (11-beta hydroxy steroiddehydrogenase type 1) inhibitors such as BVT 3498, BVT 2733, and thosedisclosed in WO 01/90091, WO 01/90090, WO 01/90092, U.S. Pat. No.6,730,690 and US 2004-0133011; (58) aminorex; (59) amphechloral; (60)amphetamine; (61) benzphetamine; (62) chlorphentermine; (63)clobenzorex; (64) cloforex; (65) clominorex; (66) clortermine; (67)cyclexedrine; (68) dextroamphetamine; (69) diphemethoxidine, (70)N-ethylamphetamine; (71) fenbutrazate; (72) fenisorex; (73) fenproporex;(74) fludorex; (75) fluminorex; (76) furfurylmethylamphetamine; (77)levamfetamine; (78) levophacetoperane; (79) mefenorex; (80)metamfepramone; (81) methamphetamine; (82) norpseudoephedrine; (83)pentorex; (84) phendimetrazine; (85) phenmetrazine; (86) picilorex; (87)phytopharm 57; and (88) zonisamide, (89) neuromedin U and analogs orderivatives thereof, (90) oxyntomodulin and analogs or derivativesthereof, and (91) Neurokinin-1 receptor antagonists (NK-1 antagonists)such as the compounds disclosed in: U.S. Pat. Nos. 5,162,339, 5,232,929,5,242,930, 5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,496,833, and5,637,699.

In another embodiment, the subject compound may be employed incombination with an anti-depressant or anti-anxiety agent, includingnorepinephrine reuptake inhibitors (including tertiary amine tricyclicsand secondary amine tricyclics), selective serotonin reuptake inhibitors(SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors ofmonoamine oxidase (RIMAs), serotonin and noradrenaline reuptakeinhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists,α-adrenoreceptor antagonists, neurokinin-1 receptor antagonists,atypical anti-depressants, benzodiazepines, 5-HT_(1A) agonists orantagonists, especially 5-HT_(1A) partial agonists, and corticotropinreleasing factor (CRF) antagonists. Specific agents include:amitriptyline, clomipramine, doxepin, imipramine and trimipramine;amoxapine, desipramine, maprotiline, nortriptyline and protriptyline;citalopram, duloxetine, fluoxetine, fluvoxamine, paroxetine andsertraline; isocarboxazid, phenelzine, tranylcypromine and selegiline;moclobemide: venlafaxine; aprepitant; bupropion, lithium, nefazodone,trazodone and viloxazine; alprazolam, chlordiazepoxide, clonazepam,chlorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam;buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceuticallyacceptable salts thereof.

In another embodiment, the subject compound may be employed incombination with anti-Alzheimer's agents; beta-secretase inhibitors,such as verubecestat; gamma-secretase inhibitors; growth hormonesecretagogues; recombinant growth hormone; HMG-CoA reductase inhibitors;NSAID's including ibuprofen; vitamin E; anti-amyloid antibodies; CB-1receptor antagonists or CB-1 receptor inverse agonists; antibiotics suchas doxycycline and rifampin; N-methyl-D-aspartate (NMDA) receptorantagonists, such as memantine; cholinesterase inhibitors such asgalantamine, rivastigmine, donepezil, and tacrine; growth hormonesecretagogues such as ibutamoren, ibutamoren mesylate, and capromorelin;histamine H₃ antagonists; AMPA agonists; PDE IV inhibitors; GABA_(A)inverse agonists; or neuronal nicotinic agonists.

In another embodiment, the subject compound may be employed incombination with sedatives, hypnotics, anxiolytics, antipsychotics,antianxiety agents, cyclopyrrolones, imidazopyridines,pyrazolopyrimidines, minor tranquilizers, melatonin agonists andantagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2antagonists, and the like, such as: adinazolam, allobarbital, alonimid,alprazolam, amitriptyline, amobarbital, amoxapine, bentazepam,benzoctamine, brotizolam, bupropion, busprione, butabarbital,butalbital, capuride, carbocloral, chloral betaine, chloral hydrate,chlordiazepoxide, clomipramine, clonazepam, cloperidone, clorazepate,clorethate, clozapine, cyprazepam, desipramine, dexclamol, diazepam,dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam,ethchlorvynol, etomidate, fenobam, flunitrazepam, flurazepam,fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam,hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline,mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone,midaflur, midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline,oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine,perphenazine, phenelzine, phenobarbital, prazepam, promethazine,propofol, protriptyline, quazepam, reclazepam, roletamide, secobarbital,sertraline, suproclone, temazepam, thioridazine, tracazolate,tranylcypromaine, trazodone, triazolam, trepipam, tricetamide,triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam,venlafaxine, zaleplon, zolazepam, zolpidem, and salts thereof, andcombinations thereof, and the like, or the subject compound may beadministered in conjunction with the use of physical methods such aswith light therapy or electrical stimulation.

In another embodiment, the subject compound may be employed incombination with levodopa (with or without a selective extracerebraldecarboxylase inhibitor such as carbidopa or benserazide),anticholinergics such as biperiden (optionally as its hydrochloride orlactate salt) and trihexyphenidyl (benzhexol) hydrochloride, COMTinhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2aadenosine receptor antagonists, cholinergic agonists, NMDA receptorantagonists, serotonin receptor antagonists and dopamine receptoragonists such as alentemol, bromocriptine, fenoldopam, lisuride,naxagolide, pergolide and pramipexole.

In another embodiment, the subject compound may be employed incombination with acetophenazine, alentemol, benzhexol, bromocriptine,biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam,fenoldopam, fluphenazine, haloperidol, levodopa, levodopa withbenserazide, levodopa with carbidopa, lisuride, loxapine, mesoridazine,molindolone, naxagolide, olanzapine, pergolide, perphenazine, pimozide,pramipexole, risperidone, sulpiride, tetrabenazine, trihexyphenidyl,thioridazine, thiothixene or trifluoperazine.

In another embodiment, the subject compound may be employed incombination with a compound from the phenothiazine, thioxanthene,heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine andindolone classes of neuroleptic agent. Suitable examples ofphenothiazines include chlorpromazine, mesoridazine, thioridazine,acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitableexamples of thioxanthenes include chlorprothixene and thiothixene. Anexample of a dibenzazepine is clozapine. An example of a butyrophenoneis haloperidol. An example of a diphenylbutylpiperidine is pimozide. Anexample of an indolone is molindolone. Other neuroleptic agents includeloxapine, sulpiride and risperidone.

In another embodiment, the subject compound may be employed incombination with a nicotine agonist or a nicotine receptor partialagonist such as varenicline, opioid antagonists (e.g., naltrexone(including naltrexone depot), antabuse, and nalmefene), dopaminergicagents (e.g., apomorphine), ADD/ADHD agents (e.g., methylphenidatehydrochloride (e.g., Ritalin® and Concerta®), atomoxetine (e.g.,Strattera®), a monoamine oxidase inhibitor (MAOI), amphetamines (e.g.,Adderall®)) and anti-obesity agents, such as apo-B/MTP inhibitors,11Beta-hydroxy steroid dehydrogenase-1 (11Beta-HSD type 1) inhibitors,peptide YY3-36 or analogs thereof, MCR-4 agonists, CCK-A agonists,monoamine reuptake inhibitors, sympathomimetic agents, β3 adrenergicreceptor agonists, dopamine receptor agonists, melanocyte-stimulatinghormone receptor analogs, 5-HT2c receptor agonists, melaninconcentrating hormone receptor antagonists, leptin, leptin analogs,leptin receptor agonists, galanin receptor antagonists, lipaseinhibitors, bombesin receptor agonists, neuropeptide-Y receptorantagonists (e.g., NPY Y5 receptor antagonists), thyromimetic agents,dehydroepiandrosterone or analogs thereof, glucocorticoid receptorantagonists, other orexin receptor antagonists, such as suvorexant,glucagon-like peptide-1 receptor agonists, ciliary neurotrophic factors,human agouti-related protein antagonists, ghrelin receptor antagonists,histamine 3 receptor antagonists or inverse agonists, and neuromedin Ureceptor agonists, and pharmaceutically acceptable salts thereof.

In another embodiment, the subject compound may be employed incombination with an anoretic agent such as aminorex, amphechloral,amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex,clominorex, clortermine, cyclexedrine, dexfenfluramine,dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine,fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex,fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane,mazindol, mefenorex, metamfepramone, methamphetamine,norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine,phentermine, phenylpropanolamine, picilorex and sibutramine; selectiveserotonin reuptake inhibitor (SSRI); halogenated amphetaminederivatives, including chlorphentermine, cloforex, clortermine,dexfenfluramine, fenfluramine, picilorex and sibutramine; andpharmaceutically acceptable salts thereof.

In another embodiment, the subject compound may be employed incombination with an opiate agonist, a lipoxygenase inhibitor, such as aninhibitor of 5-lipoxygenase, a cyclooxygenase inhibitor, such as acyclooxygenase-2 inhibitor, an interleukin inhibitor, such as aninterleukin-1 inhibitor, an NMDA antagonist, an inhibitor of nitricoxide or an inhibitor of the synthesis of nitric oxide, a non-steroidalantiinflammatory agent, or a cytokine-suppressing antiinflammatoryagent, for example with a compound such as acetaminophen, asprin,codiene, fentanyl, ibuprofen, indomethacin, ketorolac, morphine,naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl,sunlindac, tenidap, and the like. Similarly, the subject compound may beadministered with a pain reliever; a potentiator such as caffeine, anH2-antagonist, simethicone, aluminum or magnesium hydroxide; adecongestant such as phenylephrine, phenylpropanolamine, pseudophedrine,oxymetazoline, ephinephrine, naphazoline, xylometazoline,propylhexedrine, or levo-desoxy-ephedrine; an antiitussive such ascodeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; adiuretic; and a sedating or non-sedating antihistamine.

The compounds of the present invention may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. In addition to thetreatment of warm-blooded animals such as mice, rats, horses, cattle,sheep, dogs, cats, monkeys, etc., the compounds of the invention may beeffective for use in humans.

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in dosage unit form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active object compound is included inan amount sufficient to produce the desired effect upon the process orcondition of diseases. As used herein, the term “composition” isintended to encompass a product comprising the specified ingredients inthe specified amounts, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts.

Pharmaceutical compositions intended for oral use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions and such compositions may contain one ormore agents selected from the group consisting of sweetening agents,flavoring agents, coloring agents and preserving agents in order toprovide pharmaceutically elegant and palatable preparations. Tabletscontain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for examplestarch, gelatin or acacia, and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. Compositions for oral use may also be presented as hardgelatin capsules wherein the active ingredient is mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin, or as soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, for example peanut oil, liquidparaffin, or olive oil. Aqueous suspensions contain the active materialsin admixture with excipients suitable for the manufacture of aqueoussuspensions. Oily suspensions may be formulated by suspending the activeingredient in a suitable oil. Oil-in-water emulsions may also beemployed. Dispersible powders and granules suitable for preparation ofan aqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives. Pharmaceutical compositions of thepresent compounds may be in the form of a sterile injectable aqueous oroleagenous suspension. The compounds of the present invention may alsobe administered in the form of suppositories for rectal administration.For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compounds of the present invention may be employed.The compounds of the present invention may also be formulated foradministered by inhalation. The compounds of the present invention mayalso be administered by a transdermal patch by methods known in the art.

Several methods for preparing the compounds of this invention areillustrated in the following Schemes and Examples. Starting materialsare made according to procedures known in the art (e.g. PCT PatentPublications WO2001/68609, WO2004/085403, WO2005/118548, WO2008/147518,WO2009/143033 and WO2010/048012) or as illustrated herein. The followingabbreviations are used herein: Me: methyl; Et: ethyl; t-Bu: tert-butyl;Ar: aryl; Ph: phenyl; BINAP:2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; Bn: benzyl; Ac: acetyl;Boc: tert-butyloxy carbonyl; BSA: bovine serum albumin; CbzCl:benzylchloroformate; CDI: carbonyl diimidazole; DCM: dichloromethane;DCE: dichloroethane; DEAD: diethylazodicarboxylate; DIPEA:N,N-diisopropylethylamine; DMF: N,N-dimethylformamide; DMSO:dimethylsulfoxide; CH₂Cl₂: dichloromethane; EDC:N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide; Et₃N: triethylamine;EtOAc: ethyl acetate; EtOH: ethanol; HCl: hydrogen chloride; HOAt:1-hydroxy-7-aza-benzotriazole; HOBT: hydroxybenzotriazole hydrate; HPLC:high performance liquid chromatography; Hunig's base:N,N-diisopropylethylamine; MeOH: methanol; MgSO₄: magnesium sulfate;MTBE: methyl tert-butyl ether; NaHCO₃: sodium bicarbonate; NaOH: sodiumhydroxide; NMM: N-methylmorpholine; PtO₂: platinum oxide; PyClu:1-(chloro-1-pyrrolidinylmethylene)-pyrrolidinium hexafluorophosphate;rt: room temperature; SOCl₂: thionyl chloride; T3P:2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide; THF:tetrahydrofuran; TFA: trifluoracetic acid; X-Phos:2-(dicyclohexyl-phosphino)-2′,4′,6′-triisopropylbiphenyl. The compoundsof the present invention can be prepared in a variety of fashions.

In some cases the final product may be further modified, for example, bymanipulation of substituents. These manipulations may include, but arenot limited to, reduction, oxidation, alkylation, acylation, andhydrolysis reactions which are commonly known to those skilled in theart. In some cases the order of carrying out the foregoing reactionschemes may be varied to facilitate the reaction or to avoid unwantedreaction products. The following examples are provided so that theinvention might be more fully understood. These examples areillustrative only and should not be construed as limiting the inventionin any way.

INTERMEDIATES Intermediate A 2-(1-Cyanocyclopropyl)benzoic acid

Step 1: Methyl 2-(1-cyanocyclopropyl)benzoate (A2)

To a solution of NaH (1.1 g, 26.2 mmol) in DMSO (20 mL) was addedcompound A1 (2 g, 11.4 mmol); after stirring at RT under nitrogen for 1h, 1-bromo-2-chloroethane (1.8 g, 12.6 mmol) was added and the mixturestirred at RT for 2 h. The mixture was quenched with ice water (10 mL)and extracted with EtOAc (10 mL×3). The organic layers were combined,dried, and concentrated in vacuo to give the crude compound, which waspurified by silica gel column chromatography (4.8% EtOAc in petroleumether) to give the title compound as a solid. MS (ESI) m/e (M+H+) wasdetected.

Step 2: 2-(1-Cyanocyclopropyl)benzoic acid

A solution of compound A2 in THF/MeOH/H₂O (3:1:1, 16 mL) was treatedwith lithium hydroxide in water (3 mL). The mixture was stirredovernight at RT. The THF and MeOH were removed in vacuo and theresulting solution acidified to pH ˜1 with 1N HCl to give a whitecrystalline precipitate. The crystals were isolated by filtration,washed with water, and dried in vacuo affording intermediate A as asolid. MS (ESI) m/e (M+H⁺): 187.9.

Intermediate B 2-(2H-Tetrazol-2-yl)benzoic acid

To a 20 mL microwave tube was charged 2-iodobenzoic acid (1.85 g, 7.46mmol), cesium carbonate (4.06 g, 12.5 mmol), copper(I) iodide (0.128 g,0.671 mmol), and DMA (8.0 mL). N,N′-Dimethylglycine (0.131 g, 1.27 mmol)and tetrazole (1.29 g, 18.4 mmol) were added, and the solution wasirradiated at 100° C. for 1 h. The reaction was diluted with water and1N aqeous sodium hydroxide and washed with EtOAc. The aqueous fractionwas acidified with conc. HCl and extracted 2× with EtOAc. The combinedorganic fractions were washed with brine, dried over MgSO₄, filtered,and concentrated in vacuo. The residue was purified by silica gel columnchromatography [0-85% (1% acetic acid in EtOAc) in hexanes], providingthe title compound. ¹H NMR (400 MHz, CD₃OD): δ 7.72-7.84 (m, 3 H), 8.07(dd, J=7.6, 1.6 Hz, 1 H), 8.90 (s, 1 H) ppm. LRMS m/z (M+H) 191.1 found,191.2.

Intermediate C 2-(2H)-1,2,3-Triazol-2-yl)thiophene-3-carboxylic acid

A solution of 2-bromo-3-thiophene carboxylic acid (1.50 g, 7.24 mmol),1H-1,2,3-triazole (0.600 g, 8.69 mmol), potassium carbonate (2.00 g,14.5 mmol), and copper iodide (0.138 g, 0.724 mmol) in DMF (36.2 mL) waspurged subsurface with nitrogen and heated at 75° C. for 96 h. Thereaction was diluted with water, washed with ether, and acidified withconc. HCl. The acidic aqueous solution was extracted 3× with EtOAc andthe combined organic fractions were washed with brine, dried over MgSO₄,filtered, and concentrated in vacuo. The crude material was purified bysilica gel column chromatography [0-70% (1% acetic acid in EtOAc) inhexanes], providing the title compound as a solid. LRMS m/z (M+H) 196.2found, 196.1 required.

Intermediate D Potassium 2-(pyrimidin-2-yl)thiophene-3-carboxylate

A solution of 2-bromo-3-thiophene carboxylic acid (3.35 g, 16.2 mmol) inmethanol (50 mL) was cooled to 0° C. and saturated with gaseous HCl. Thesolution was heated at 60° C. overnight, then concentrated in vacuo. Theresidue was redissolved in EtOAc, washed with saturated, aqueous NaHCO₃and brine, dried over Na₂SO₄, filtered, and concentrated in vacuo,providing methyl 2-bromothiophene-3-carboxylate as a oil. LRMS m/z (M+H)221.1 found, 221.0 required. A solution of methyl2-bromothiophene-3-carboxylate (1.74 g, 7.87 mmol),2-(tributylstannyl)pyrimidine (4.36 g, 11.81 mmol), cesium fluoride(4.78 g, 31.5 mmol), and copper(I) iodide (0.450 g, 2.36 mmol) in DMF(16 mL) in a pressure vessel was purged subsurface with nitrogen andtreated with palladium tetrakis (0.455 g, 0.394 mmol). The mixture wassealed and heated at 120° C. overnight. The reaction was partitionedbetween EtOAc and water and filtered through celite. The organic layerwas washed with saturated, aqueous NaHCO₃ and brine, dried over MgSO₄,filtered, and concentrated in vacuo. The residue was purified by silicagel column chromatography (0-30% EtOAc in hexanes), providing methyl2-(pyrimidin-2-yl)thiophene-3-carboxylate as a solid. LRMS m/z (M+H)221.2 found, 221.1 required. A solution of methyl2-(pyrimidin-2-yl)thiophene-3-carboxylate (0.695 g, 3.16 mmol) andpotassium trimethylsilanolate (0.506 g, 3.94 mmol) in THF (16 mL) wasstirred at RT overnight, then diluted with ether and filtered through aglass frit. The solids were washed with ether and concentrated,providing the title compound as a solid. LRMS m/z (M+H) 207.3 found,207.1 required.

Intermediate E 4-[1,2,3]Triazol-2-yl-thiophene-3-carboxylic acid

Step 1: 4-Bromo-thiophene-3-carboxylic acid ethyl ester (E1)

To a solution of 3,4-dibromothiophene (30 g, 0.12 mol) in THF (200 mL)at 0° C. was added i-PrMgCl (2.0 M solution in THF, 77 mL, 0.15 mol),keeping the temperature below 5° C. The resulting mixture was stirred at0-5° C. for 5 h and then ethyl chloroformate (14.4 mL, 0.15 mol) wasadded dropwise at <10° C. and the resulting mixture was warmed to RT,stirred overnight, and quenched with saturated, aqueous NH₄Cl. Most ofthe THF was then removed in vacuo, water was added, and the mixture wasextracted with EtOAc (80 mL×4). The combined organic layers were driedover Na₂SO₄, filtered, the filtrate concentrated in vacuo, and the crudeproduct was purified by silica gel column chromatography (petroleumether:EtOAc=300:1) to provide the title compound as a oil.

Step 2: 4-Bromo-thiophene-3-carboxylic acid (E2)

To a solution of the product from Step 1 (10 g, 43 mmol) in methanol (60mL) was added sodium hydroxide (3.4 g, 86 mmol) and water (1 mL) and themixture was stirred at RT overnight. The mixture was concentrated invacuo. The residue was diluted with water (30 mL) and extracted withEtOAc (25 mL×4). The pH of aqueous layer was adjusted to ˜3 with 1N HCland extracted with EtOAc (25 mL×4). The combined extracts were driedover Na₂SO₄, filtered, and concentrated in vacuo to provide the titlecompound as a solid. LRMS m/z (M+H) 206.9, 208.9 found, 206.9, 208.9required.

Step 3: 4-[1,2,3]Triazol-2-yl-thiophene-3-carboxylic acid (IntermediateE)

To a mixture of the product from Step 2 (7.9 g, 38 mmol), Cs₂CO₃ (24.8g, 76 mmol), and CuI (2.88 g, 7.6 mmol) in DMF (200 mL) was added2H-[1,2,3]triazole (5.24 g, 76 mmol) andN,N′-dimethyl-cyclohexane-1,2-diamine (0.9 g, 6.5 mmol) and the mixturewas stirred at 110° C. overnight. The cooled mixture was adjusted to ˜pH12 with 1N sodium hydroxide and extracted with EtOAc (50 mL×3). Theaqueous layer was adjusted to ˜pH 4 with 1N HCl and extracted with EtOAc(50 mL×4). The extracts were dried over Na₂SO₄, filtered, the filtrateconcentrated in vacuo, and the residue was purified by silica gel columnchromatography (petroleum ether:EtOAc=10:1) to provide the titlecompound. LRMS m/z (M+H) 196.0 found, 196.0 required.

Intermediate F 4-Fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid

To a mixture of 2-bromo-4-fluorobenzoic acid (30 g, 137 mmol), cesiumcarbonate (89.26 g, 274 mmol), and CuI (5.27 g, 27.4 mmol) in DMF (200mL) was added N,N′-dimethylcyclohexane-1,2-diamine (3.7 mL, 23.3 mmol)and 1H-1,2,3-triazole (18.92 g, 274 mmol). The resulting mixture wasstirred at 110° C. overnight, cooled, concentrated in vacuo, and dilutedwith water (150 mL). The aqueous layer was washed with EtOAc (300 mL×3).The aqueous layer was acidified with 2N HCl and extracted with EtOAc(300 mL×4). The combined organic layers were washed with brine (150mL×3), dried over Na₂SO₄, filtered, and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (petroleumether:EtOAc=100:1˜5:1) to provide the title compound as a solid. LRMSm/z (M+H) 208.0 found, 208.0 required.

Intermediate G 2-(2,2-Difluoroethoxy)nicotinic acid

To a suspension of 2,2-difluoroethanol (492 mg, 6.0 mmol) in DMF (10 mL)at 0° C. was added NaH (180 mg, 4.5 mmol) and the mixture was stirred at0° C. for 0.5 h. A suspension of 2-fluoronicotinic acid (423 mg, 3.0mmol) and NaH (180 mg, 4.5 mmol) in DMF (5 mL) was added dropwise at 0°C. and the resulting mixture was stirred at RT overnight. The mixturewas diluted with water, acidified to pH˜3 with 1N HCl, and extractedwith EtOAc (50 mL×3). The combined organic layers were washed withbrine, dried over MgSO₄, filtered, and concentrated in vacuo to give thecrude product which was used without further purification. LRMS m/z(M+H) 204.1 found, 204.0 required.

The following intermediates were made as described above, replacing2,2-difluoroethanol with the appropriate alcohol.

Example 1

N-Ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)ethyl)-2-(2H-1,2,3-triazol-2-yl)benzamideStep 1: N-Ethyl-N-(2-hydroxyethyl)-2-(2H-1,2,3-triazol-2-yl)benzamide(1)

A solution of 2-(2H-1,2,3-triazol-2-yl)benzoic acid (2.10 g, 11.2 mmol)in SOCl₂ (30 mL) was stirred at 80° C. for 2 h. After cooling to RT, themixture was concentrated in vacuo. To a mixture of 2-(ethylamino)ethanol(997 mg, 11.2 mmol) and DIEA (4.30 g, 336. mmol) in DCM (15 mL) at 0° C.was added dropwise the above residue. The resulting mixture was stirredat RT for 3 h, then quenched with water (50 mL) and extracted with EtOAc(80 mL×3). The organic layers were combined, dried over MgSO₄, filtered,and concentrated in vacuo. The residue was purified by silica gel columnchromatography (50% EtOAc in petroleum ether) to give the title compoundas a oil. LRMS m/z (M+H) 261.3 found, 261.1 required.

Step 2: Methyl2-(2-(N-ethyl-2-(2H-1,2,3-triazol-2-yl)benzamido)ethyl)-2H-1,2,3-triazole-4-carboxylate(2)

To a solution of the product from Step 1 (800 mg, 3.07 mmol), methyl2H-1,2,3-triazole-4-carboxylate (469 mg, 3.69 mmol), andtriphenylphosphine (967 mg, 3.69 mmol) in THF (5 mL) was added asolution of (E)-di-tert-butyl diazene-1,2-dicarboxylate (920 mg, 4.00mmol) in THF (4 mL) dropwise. The resulting mixture was stirred at RTovernight, then quenched with water and extracted with EtOAc (100 mL×3).The organic layers were combined, washed with brine, dried over MgSO₄,filtered, and concentrated in vacuo. The residue was purified by silicagel column chromatography (50% EtOAc in petroleum ether) to give thetitle compound as a solid. LRMS m/z (M+H) 370.1 found, 370.2 required.

Step 3:N-Ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)ethyl)-2-(2H-1,2,3-triazol-2-yl)benzamide

To a solution of the product from Step 2 (100 mg, 0.27 mmol) in THF (3mL) was added MeMgBr (3 M in ether, 0.27 mL, 0.81 mmol) at 0° C. underN₂. The mixture was stirred at the same temperature for 2 h. The mixturewas quenched with saturated, aqueous NH₄Cl and extracted with EtOAc (20mL×3). The organic layers were combined, dried over MgSO₄, filtered, andconcentrated in vacuo. The residue was purified by prep-HPLC to give thetitle compound as a oil. LRMS m/z (M-OH) 352.2 found, 370.2 required.

Example 2 and Example 3

N-Ethyl-N-(2-(4-(2-hydroxybutan-2-yl)-2H-1,2,3-triazol-2-yl)ethyl)-2-(2H-1,2,3-triazol-2-yl)benzamideandN-Ethyl-N-(2-(4-(1-hydroxyethyl)-2H-1,2,3-triazol-2-yl)ethyl)-2-(2H-1,2,3-triazol-2-yl)benzamideStep 1:2-(2-(N-ethyl-2-(2H-1,23-triazol-2-yl)benzamido)ethyl)-2H-1,2,3-triazole-4-carboxylicacid (3)

To a solution of compound 2 (1.0 g, 2.71 mmol, Example 1, Step 2) inMeOH (10 mL) and water (5 mL) was added LiOH (hydrate, 0.34 g, 8.12mmol). The resulting mixture was stirred at RT overnight. The mixturewas concentrated in vacuo to remove most of the MeOH. The aqueousmixture was diluted with water (20 mL) and adjusted to ˜pH 3 with 1N HCland extracted with DCM (20 mL×3). The combined organic layers wereconcentrated in vacuo to give the title compound as a solid. LRMS m/z(M+H) 356.1 found, 356.1 required.

Step 2:2-(2-(N-Ethyl-2-(2H-1,2,3-triazol-2-yl)benzamido)ethyl)-N-methoxy-N-methyl-2H-1,2,3-triazole-4-carboxamide(4)

To a solution of the product from Step 1 (900 mg, 2.53 mmol) in DCM (10mL) was added HATU (1252 mg, 3.29 mmol) TEA (1.412 ml, 10.13 mmol). Themixture was stirred at RT for 30 mins and then N,O-dimethylhydroxylamine(201 mg, 3.29 mmol) was added. The mixture was stirred at RT for 5 h,then quenched with water (50 mL) and extracted with EtOAc (50 mL×3). Thecombined organic layers were dried over MgSO₄, filtered, andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (66% EtOAc in petroleum ether) to give the title compoundas a solid. LRMS m/z (M+H) 399.1 found, 399.2 required.

Step 3:N-(2-(4-Acetyl-2H-1,2,3-triazol-2-yl)ethyl)-N-ethyl-2-(2H-1,2,3-triazol-2-yl)benzamide(5)

To a solution of the product from Step 2 (1 g, 2.510 mmol) in dry THF (2mL) at −70° C. was added CH3MgBr (3 M in ether, 2.5 mL, 7.53 mmol)dropwise. The mixture was stirred at −70° C. for 3 h, then quenched withwater (20 mL) and extracted with EtOAc (100 mL×3). The combined organiclayers were dried over MgSO₄ and filtered. Concentrated in vacuo. Theresidue was purified by prep-HPLC to give the title compound as a solid.LRMS m/z (M+H) 354.1 found, 354.2 required.

Step 4:N-Ethyl-N-(2-(4-(2-hydroxybutan-2-yl)-2H-1,2,3-triazol-2-yl)ethyl)-2-(2H-1,2,3-triazol-2-yl)benzamide(Example 2) &N-Ethyl-N-(2-(4-(2-hydroxybutan-2-yl)-2H-1,2,3-triazol-2-yl)ethyl)-2-(2H-1,2,3-triazol-2-yl)benzamide(Example 3)

To a solution of the product from Step 3 (100 mg, 0.283 mmol) in dry THF(3 mL) at −70° C. was added a solution of EtMgBr (37.7 mg, 0.283 mmol)dropwise. The mixture was stirred at −70° C. for 3 h. The mixture wasquenched with water (20 mL) and extracted with EtOAc (100 mL×3). Thecombined organic layers were dried over MgSO₄ and filtered. Concentratedin vacuo. The residue was purified by prep-HPLC to give Example 2 andExample 3 as solids. Example 2: LRMS m/z (M-OH) 366.4 (M-OH) found,384.2 required. Example 3: LRMS m/z (M-OH) 338.1, 356.1 (M+H) found,356.2 required.

Example 4

2-Cyclopropyl-N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)ethyl)benzamideStep 1: Benzyl ethyl(2-hydroxyethyl)carbamate (6)

To a solution of 2-(ethylamino)ethanol (5.0 g, 56.1 mmol) in THF/water(30 ml/30 mL) was added NaHCO₃ (9.42 g, 112 mmol) at 0° C. The mixturewas stirred at 0° C. for 30 mins and then Cbz-Cl (10.5 g, 61.7 mmol) wasadded dropwise at 0° C. The resulting mixture was stirred at RTovernight, then quenched with water (20 mL) and extracted with EtOAc (50mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄, filtered, and concentrated in vacuo. The residue was purified bysilica gel column chromatography (10%-30% EtOAc in petroleum ether),providing the title compound as a oil. LRMS m/z (M+H) 224.1 found, 224.1required.

Step 2: Methyl2-(2-(((benzyloxy)carbonyl)(ethyl)amino)ethyl)-2H-1,2,3-triazole-4-carboxylate(7)

To a solution of the product from Step 1 (9.5 g, 42.5 mmol), methyl2H-1,2,3-triazole-4-carboxylate (6.49 g, 51.1 mmol), and PPh₃ (16.7 g,63.8 mmol) in THF (100 mL) was added a solution of DIAD (19.6 g, 85.0mmol) in THF dropwise at 0° C. under N₂. The resulting mixture wasstirred at RT overnight. Water was added to quench the reaction and themixture was extracted with EtOAc (50 mL×3). The combined organic layerswere dried over MgSO₄, filtered, and concentrated in vacuo. The residuewas purified by silica gel column chromatography (10%-50% EtOAc inpetroleum ether), providing the title compound as a oil. LRMS m/z (M+H)333.1 found, 333.1 required.

Step 3: Benzylethyl(2-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)ethyl)carbamate(8)

To a solution of the product from Step 2 (3.0 g, 9.03 mmol) in THF (30mL) was added MeMgBr (3 M in ether, 5.3 mL, 15.9 mmol) dropwise at 0° C.The mixture was stirred at RT for 3 h, then quenched with saturated,aqueous NH₄Cl and extracted with EtOAc (30 mL×3). The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (10%-30% EtOAc in petroleum ether) to give the titlecompound as a oil. LRMS m/z (M+H) 333.1 found, 333.1 required.

Step 4: 2-(2-(2-(ethylamino)ethyl)-2H-1,2,3-triazol-4-yl)propan-2-ol (9)

To a solution of the product from Step 3 (2.0 g, 6.02 mmol) in THF (20mL) was added Pd/C (10 wt %, 192 mg). The mixture was stirred at RTunder a hydrogen balloon overnight, filtered, and concentrated in vacuoto give the title compound as a oil. LRMS m/z (M+H) 199.1 found, 199.1required.

Step 5:2-Cyclopropyl-N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)ethyl)benzamide(10)

To a solution of the product from Step 4 (67.3 mg, 0.34 mmol) in DCM (3mL) was added DIEA (120 mg, 0.93 mmol), HATU (129 mg, 0.34 mmol), and2-cyclopropylbenzoic acid (50 mg, 0.31 mmol). The resulting mixture wasstirred at RT overnight, then quenched with water (20 mL) and extractedwith DCM (20 mL×3). The combined organic layers were washed with brine,dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue waspurified by prep-HPLC to give title compound as a oil. LRMS m/z (M+H)325.4 (M-OH) found, 343.2 required.

TABLE 1 The following compounds were prepared according to the generalprocedure provided in Example 4 and procedures herein. The startingmaterials are either prepared as described in the intermediates section,commercially available, or may be prepared from commercially availablereagents using conventional reactions well known in the art. Ex.Structure Name Mass [M + H]  5

N-ethyl-N-(2-(4-(2- hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)ethyl)-2-(pyrrolidin- 1-yl)benzamide Calc'd (M + Na + MeCN)435.2, found 435.3 11

N-ethyl-N-(2-(4-(2- hydroxypropan-2-yl)-2H-1,2,3- triazol-2-yl)ethyl)-2-((trifluoromethyl)thio)benzamide Calc'd 403.1, found 403.2 12

N-ethyl-N-(2-(4-(2- hydroxypropan-2-yl)-2H-1,2,3- triazol-2-yl)ethyl)-2-(trifluoromethoxy)benzamide Calc'd (M + Na) 409.1, found (M − OH) 369.2(M + Na) 409.2 18

N-ethyl-N-(2-(4-(2- hydroxypropan-2-yl)-2H-1,2,3- triazol-2-yl)ethyl)-2-isopropoxybenzamide Calc'd 361.2, found 361.2

Example 20

N-Ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-2-(2H-1,2,3-triazol-2-yl)benzamideStep 1: Ethyl2-(2-(N-ethyl-2-(2H-1,2,3-triazol-2-yl)benzamido)ethyl)-5-methyl-2H-1,2,3-triazole-4-carboxylate(10)

To a solution of compound 1 (263 mg, 1.01 mmol, Step 1 in Example 1),ethyl 5-methyl-2H-1,2,3-triazole-4-carboxylate (130 mg, 0.839 mmol), andPPh₃ (442 mg, 1.68 mmol) in dry THF (5 mL) was added DIAD (440 mg, 7.29mmol) at 0° C. The mixture was stirred at RT for 4 h. The mixture wasconcentrated in vacuo and the residue was purified by silica gel columnchromatography (0˜50% EtOAc in petroleum ether) to give the titlecompound as a solid. LCMS m/z (M+H) 398.2 found, 398.2 required.

Step 2:2-(2-(N-Ethyl-2-(2H-1,2,3-triazol-2-yl)benzamido)ethyl)-5-methyl-2H-1,2,3-triazole-4-carboxylicacid (2)

To a solution of the product from Step 1 (250 mg, 0.630 mmol) in THF (8mL) and H₂O (2 mL) was added LiOH (hydrate, 277 mg, 6.30 mmol). Themixture was stirred at RT for 1.5 h, then concentrated in vacuo toremove THF and the aqueous layer was extracted with DCM (15 mL×2). Thecombined aqueous phase was adjusted to pH 3˜4 with 4N HCl and extractedwith EtOAc (15 mL×3). The combined organic layers were dried overNa₂SO₄, filtered, and concentrated in vacuo to give the title compoundas a oil. LCMS m/z (M+H) 370.1 found, 370.2 required.

Step 3: Methyl2-(2-(N-ethyl-2-(2H-1,2,3-triazol-2-yl)benzamido)ethyl)-5-methyl-2H-1,2,3-triazole-4-carboxylate(3)

To a solution of the product from Step 2 (200 mg, 0.542 mmol) in DCM (8mL) and MeOH (2 mL) was added TMSCH₂N₂ (2 M in n-hexane, 0.5 mL, 1.08mmol) dropwise at 0° C. The reaction mixture was stirred at RT for 2 h.The mixture was concentrated in vacuo and the residue was purified bysilica gel column chromatography (0˜50% EtOAc in petroleum ether) togive the title compound as a solid. LCMS m/z (M+H) 384.2 found, 384.2required.

Step 4:N-Ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-2-(2H-1,2,3-triazol-2-yl)benzamide

To a solution of MeMgBr (3 M in ether, 0.2 mL, 0.628 mmol) in THF (1 mL)was added a solution of the product from Step 3 (60 mg, 0.157 mmol) inTHF (2 mL) dropwise at −20° C. under N₂. The mixture was stirred at 0°C. for 2 h, then quenched with saturated, aqueous NH₄Cl and extractedwith EtOAc (20 mL×3). The organic layers were combined, dried overNa₂SO₄, filtered, and concentrated in vacuo and the residue was purifiedby prep-HPLC to give the title compound as a oil. LCMS m/z (M-OH) 366.2(M+Na) 406.2 found, 384.2 required.

Example 21

N-Ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-2-(2,2,2-trifluoroethoxy)nicotinamideStep 1: Benzyl ethyl(2-hydroxyethyl)carbamate (13)

To a solution of 2-(ethylamino)ethanol (17.8 g, 0.2 mol) in THF (300 mL)and 1N aqueous NaOH (300 mL, 0.3 mol) at 0° C. was added CbzCl (40.8 g,0.24 mol) dropwise. The resulting mixture was stirred at RT overnight.EtOAc (100 mL) was added and the organic layer was separated. Theorganic fraction was washed with brine (100 mL), dried over Na₂SO₄,filtered, and concentrated in vacuo. The residue was purified by silicagel column chromatography (33% EtOAc in petroleum ether) to give thetitle compound as a oil. LRMS m/z (M+H) 224.2 found, 224.2 required.

Step 2: Ethyl2-(2-(((benzyloxy)carbonyl)(ethyl)amino)ethyl)-5-methyl-2H-1,2,3-triazole-4-carboxylate(14)

To a solution of the product from Step 1 (5.35 g, 0.024 mol), ethyl5-methyl-2H-1,2,3-triazole-4-carboxylate (3.1 g, 0.02 mol), andPPh3(10.5 g, 0.04 mol) in THF (50 mL) at 0° C. was added DBAD (9.2 g,0.04 mol). The resulting mixture was stirred at RT under N₂ for 16 h,then concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (33% EtOAc in petroleum ether) to give the titledcompound as a oil. LRMS m/z (M+H) 361.2 found, 361.2 required.

Step 3: Benzylethyl(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)carbamate(15)

To a solution of the product from Step 2 (2.6 g, 7.2 mmol) in THF (40mL) at −10° C. was added MeMgBr solution (3 M in ether, 16 mL, 48 mmol).The resulting mixture was stirred at −10° C.˜−5° C. for 2 h, thenquenched with 15 mL of water and extracted with EtOAc (50 mL). Theorganic phase was concentrated in vacuo. The residue was purified bysilica gel column chromatography (50% EtOAc in petroleum ether) to givethe title compound as a colorless oil. LRMS m/z (M+H) 369.3 found, 369.3required.

Step 4:2-(2-(2-(Ethylamino)ethyl)-5-methyl-2H-1,2,3-triazol-4-yl)propan-2-ol(16)

To a solution of the product from Step 3 (1.9 g, 5.46 mmol) in EtOH (50mL) was added Pd/C (10 wt %, 0.19 g). The resulting mixture was under ahydrogen balloon for 16 h and then filtered and concentrated in vacuo toafford the target compound as a oil, which was used without furtherpurification. LRMS m/z (M+H) 213.2 found, 213.2 required.

Step 5:N-Ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-2-(2,2,2-trifluoroethoxy)nicotinamide(Example 21)

A mixture of 2-(2,2,2-trifluoroethoxy)nicotinic acid (50 mg, 0.21 mmol),HATU (80 mg, 0.21 mmol), and DIEA (74 mg, 0.57 mmol) in DMF (2 mL) wasstirred at RT for 10 mins, then the product from Step 4 (30 mg, 0.14mmol) was added. The resulting mixture was stirred at RT for anadditional 16 h and then filtered. The filtrate was purified byprep-HPLC to afford the title compound as a oil.

TABLE 2 The following compounds were prepared according to the generalprocedure provided in Example 21 and procedures herein. The startingmaterials are either prepared as described in the intermediates section,commercially available, or may be prepared from commercially availablereagents using conventional reactions well known in the art. Ex.Structure Name Exact Mass 22

N-ethyl-N-(2-(4-(2- hydroxypropan-2-yl)- 5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-2- isopropoxynicotinamide Calc'd (M + Na) 398.2,found (M − OH) 358.2 (M + Na) 398.2 23

2-ethoxy-N-ethyl-N- (2-(4-(2- hydroxypropan-2-yl)- 5-methyl-2H-1,2,3-triazol-2- yl)ethyl)nicotinamide Calc'd (M + Na) 384.2, found (M − OH)344.2, (M + Na) 384.2 24

2-(2,2- difluoroethoxy)-N- ethyl-N-(2-(4-(2- hydroxypropan-2-yl)-5-methyl-2H-1,2,3- triazol-2- yl)ethyl)nicotinamide Calc'd (M + Na)420.2, found (M − OH) 380.2, (M + Na) 420.1 25

2-(difluoromethoxy)- N-ethyl-N-(2-(4-(2- hydroxypropan-2-yl)-5-methyl-2H-1,2,3- triazol-2- yl)ethyl)benzamide Calc'd (M + Na) 405.2,found (M − OH) 365.2, (M + Na) 405.1 26

N-ethyl-N-(2-(4-(2- hydroxypropan-2-yl)- 5-methyl-2H-1,2,3-triazol-2-ypethyl)-2- (trifluoromethoxy) benzamide Calc'd (M + Na)423.2, found (M − OH) 383.2, (M + Na) 423.1 27

2-ethoxy-N-ethyl-N- (2-(4-(2- hydroxypropan-2-yl)- 5-methyl-2H-1,2,3-triazol-2- yl)ethyl)benzamide Calc'd (M + Na) 383.2, found (M − OH)343.2, (M + Na) 383.2 28

2-cyclopropyl-N- ethyl-N-(2-(4-(2- hydroxypropan-2-yl)-5-methyl-2H-1,2,3- triazol-2- yl)ethyl)benzamide Calc'd (M + Na) 379.2,found (M − OH) 339.1, (M + Na) 379.1 29

N-ethyl-N-(2-(4-(2- hydroxypropan-2-yl)- 5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-2- (1H-pyrazol-1- yl)benzamide Calc'd (M + Na)405.2, found (M − OH) 365.1, (M + Na) 405.1 30

N-ethyl-4-fluoro-N-(2- (4-(2-hydroxypropan- 2-yl)-5-methyl-2H-1,2,3-triazol-2- yl)ethyl)-2-(2H-1,2,3- triazol-2- yl)benzamide Calc'd(M + Na) 424.2, found (M − OH) 384.1, (M + Na) 424.1 31

N-ethyl-N-(2-(4-(2- hydroxypropan-2-yl)- 5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-2- phenylnicotinamide Calc'd (M + H) 394.2, found(M + H) 394.2 32

N-ethyl-N-(2-(4-(2- hydroxypropan-2-yl)- 5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-2- propylbenzamide Calc'd (M + Na) 381.2, found (M −OH) 341.2, (M + Na) 381.2 33

N-ethyl-N-(2-(4-(2- hydroxypropan-2-yl)- 5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-2- (2,2,2- trifluoroethoxy) benzamide Calc'd (M +Na) 437.2, found (M − H) 397.1, (M + Na) 437.1 34

N-ethyl-N-(2-(4-(2- hydroxypropan-2-yl)- 5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-2- (2,2,2- trifluoroethyl) benzamide Calc'd (M + Na)421.2, found (M − OH) 381.1, (M + Na) 421.1 35

2-(2,2- difluoroethoxy)-N- ethyl-N-(2-(4-(2- hydroxypropan-2-yl)-5-methyl-2H-1,2,3- triazol-2- yl)ethyl)benzamide Calc'd (M + Na) 419.2,found (M − OH) 379.1, (M + Na) 419.1 36

N-ethyl-N-(2-(4-(2- hydroxypropan-2-yl)- 5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-2- (2,2,2- trifluoroethyl) nicotinamide Calc'd (M +Na) 422.2, found (M − OH) 382.1, (M + Na) 422.1 37

2-(2,2-difluoroethyl)- N-ethyl-N-(2-(4-(2- hydroxypropan-2-yl)-5-methyl-2H-1,2,3- triazol-2- yl)ethyl)benzamide Calc'd (M + Na) 403.2,found (M − OH) 363.1, (M + Na) 403.1 38

2-(2,2- difluorocyclopropyl)- N-ethyl-N-(2-(4-(2- hydroxypropan-2-yl)-5-methyl-2H-1,2,3- triazol-2- yl)ethyl)benzamide Calc'd (M + Na) 415.2,found (M − OH) 375.1, (M + Na) 415.1 39

2-cyclopropyl-N- ethyl-N-(2-(4-(2- hydroxypropan-2-yl)-5-methyl-2H-1,2,3- triazol-2-yl)ethyl)-6- methoxynicotinamide Calc'd(M + Na) 410.2, found (M − OH) 370.2, (M + Na) 410.1 40

2-cyclobutyl-N-ethyl- N-(2-(4-(2- hydroxypropan-2-yl)-5-methyl-2H-1,2,3- triazol-2- yl)ethyl)benzamide Calc'd (M + Na) 393.2,found (M − OH) 353.2, (M + Na) 393.1 41

N-ethyl-N-(2-(4-(2- hydroxypropan-2-yl)- 5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-2- (pyrrolidin-1- yl)benzamide Calc'd (M + H) 386.2,found (M + H) 386.2 42

N-ethyl-N-(2-(4-(2- hydroxypropan-2-yl)- 5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-2- (2H-tetrazol-2- yl)benzamide Calc'd (M + Na)407.2, found (M − OH) 367.2, (M + Na) 407.2 43

N-ethyl-N-(2-(4-(2- hydroxypropan-2-yl)- 5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-3- (2H-1,2,3-triazol-2- yl)picolinamide Calc'd (M +Na) 407.2, found (M − OH) 367.2, (M + Na) 407.1 44

N-ethyl-N-(2-(4-(2- hydroxypropan-2-yl)- 5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-3- phenylpicolinamide Calc'd (M + H) 394.2, found(M + H) 394.2 45

N-ethyl-N-(2-(4-(2- hydroxypropan-2-yl)- 5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-3- (pyridin-2- yl)pyrazine-2- carboxamide Calc'd(M + H) 396.2, found (M + H) 396.1 47

N-ethyl-N-(2-(4-(2- hydroxypropan-2-yl)- 5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-3- (1H-pyrazol-1- yl)pyrazine-2- carboxamide Calc'd(M + Na) 407.2, found (M − OH) 367.2, (M + Na) 407.2 48

N-ethyl-N-(2-(4-(2- hydroxypropan-2-yl)- 5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-2- (1H-pyrazol-1- yl)nicotinamide Calc'd (M + Na)406.2, found (M − OH) 366.1, (M + Na) 406.1

Example 49

N-Ethyl-N-{2-[4-(1-hydroxy-1-methylethyl)-1H-pyrazol-1-yl]ethyl}-2-(2H-1,2,3-triazol-2-yl)benzamideStep 1: N-(2-Chloroethyl)-N-ethyl-2-(2H-1,2,3-triazol-2-yl)benzamide(17)

To a solution of compound 1 (700 mg, 2.69 mmol, example 1, Step 1) inDCM (5 mL) was added TEA (1.2 mL, 8.07 mmol) at 0° C. The mixture wasstirred at the same temperature for 10 mins, then methanesulfonylchloride (670 mg, 5.85 mmol) was added. The resulting mixture wasstirred at 0° C. for 2 h. The reaction was quenched with saturated,aqueous NH₄Cl and extracted with DCM (100 mL×3). The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated in vacuo togive the title compound as a oil. LRMS m/z (M+H) 279.1 found, 279.1required.

Step 2: Ethyl1-(2-(N-ethyl-2-(2H-1,2,3-triazol-2-yl)benzamido)ethyl)-1H-pyrazole-4-carboxylate(18)

A mixture of the product from Step 1 (150 mg, 0.538 mmol), methyl1H-pyrazole-3-carboxylate (102 mg, 0.807 mmol), and Cs₂CO₃ (351 mg,1.076 mmol) in DMF (2 mL) was stirred at 80° C. overnight. After coolingto RT, the mixture was diluted with water and extracted with EtOAc (100mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄, filtered, and concentrated in vacuo and the residue was purifiedby prep-TLC (50% EtOAc in petroleum ether) to give the title as a oil.LRMS m/z (M+H) 383.2 found, 383.1 required.

Step 3:N-Ethyl-N-{2-[4-(1-hydroxy-1-methylethyl)-1H-pyrazol-1-yl]ethyl}-2-(2H-1,2,3-triazol-2-yl)benzamide

To a solution of the product from Step 2 (100 mg, 0.261 mmol) in THF (2mL) was added MeMgBr (3 M in ether, 0.5 mL, 1.5 mmol) at 0° C. dropwise.The resulting mixture was stirred at RT for 1 h, then quenched withsaturated, aqueous NH₄Cl and extracted with EtOAc (50 mL×3). Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated in vacuo. The residue was purified by prep-HPLC to give thetitle compound as a oil. LRMS m/z (M+H) 351.1 (M-OH) found, 369.2required.

Example 50

N-Ethyl-N-{2-[3-(1-hydroxy-1-methylethyl)-1H-pyrazol-1-yl]ethyl}-2-(2H-1,2,3-triazol-2-yl)benzamideStep 1: Methyl1-(2-(N-ethyl-2-(2H-1,2,3-triazol-2-yl)benzamido)ethyl)-1H-Pyrazole-3-carboxylate(19)

A mixture ofN-(2-chloroethyl)-N-ethyl-2-(2H-1,2,3-triazol-2-yl)benzamide (150 mg,0.538 mmol, Example 21, Step 1), methyl 1H-pyrazole-3-carboxylate (102mg, 0.807 mmol), and Cs₂CO₃ (351 mg, 1.076 mmol) in DMF (2 mL) wasstirred at 80° C. overnight. After cooling to RT, the mixture wasdiluted with water and extracted with EtOAc (100 mL×3). The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo. The residue was purified by preparative TLC (50%EtOAc in petroleum ether) to give the title compound as a oil. LRMS m/z(M+H) 369.2 found, 369.1 required.

Step 2:N-Ethyl-N-{2-[3-(1-hydroxy-1-methylethyl)-1H-pyrazol-1-yl]ethyl}-2-(2H-1,2,3-triazol-2-yl)benzamide

To a solution of the product from Step 1 (100 mg, 0.271 mmol) in THF (2mL) was added MeMgBr (3 M in ether, 0.5 mL, 1.5 mmol) at 0° C. dropwise.The resulting mixture was stirred at RT for 1 h, then quenched withsaturated, aqueous NH₄Cl and extracted with EtOAc (50 mL×3). Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated in vacuo. The residue was purified by prep-HPLC to give thetitle compound as a oil. LRMS m/z (M+H) 351.2 (M-OH) found, 369.2required.

The following table shows representative data for the compounds of theExamples as orexin receptor antagonists as determined by the assaysdescribed herein.

TABLE 3 hOX2R FLIPR hOX1R FLIPR Example IC₅₀ (nM) IC₅₀ (nM) 1 58 >10,0002 65 >10,000 3 373 >10,000 4 47 >10,000 5 41 >10,000 11 34 >10,000 12247 >10,000 18 145 >10,000 20 12 2855 21 21 >10,000 22 61 >10,000 2358 >10,000 24 44 >10,000 25 35 >10,000 26 19 >10,000 27 27 >10,000 28 131561 29 28 >10,000 30 10 5539 31 33 >10,000 32 32 2207 33 52 >10,000 3437 >10,000 35 35 >10,000 36 270 >10,000 37 10 >10,000 38 10 1481 39 142843 40 13 1174 41 15 2103 42 29 >10,000 43 180 >10,000 44 106 >10,00045 87 >10,000 47 239 >10,000 48 13 7521 49 35 >10,000 50 23 >10,000

As indicated by the data herein, the compounds of the present examplesprovide greater functional selectivity for the orexin-2 receptor overthe orexin-1 receptor. The distinction in potency between the orexin-2receptor and the orexin-1 receptor in the whole cell FLIPR functionalassay provides enhanced predictive value for determining in vivoefficacy. Increasing the functional selectivity for the orexin-2receptor reduces the potential for dual receptor antagonism in vivo.Such greater functional selectivity may provide benefits over otherorexin receptor antagonists that are known in the art.

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.

What is claimed is:
 1. A compound of the formula I:

wherein: A is phenyl; X is N: R^(1a) and R^(1b) are independentlyselected from the group consisting of: (1) hydrogen, (2) halogen, (3)hydroxyl, (4) C₁₋₆alkyl, which is unsubstituted or substituted withhalogen, hydroxyl or phenyl, (5) —O—C₁₋₆alkyl, which is unsubstituted orsubstituted with halogen, hydroxyl or phenyl, (6) —CN, and (7)heteroaryl, wherein heteroaryl is selected from imidazolyl, indolyl,oxazolyl, pyridyl, pyrrolyl, pyrimidinyl, tetrazolyl, and triazolyl,which is unsubstituted or substituted with halogen, hydroxyl, C₁₋₆alkyl,—O—C₁₋₆alkyl or-NO₂, and R^(1c) is hydrogen; R³ is ethyl; R⁵ is—C(CH₃)₂OH; R⁶ is selected from the group consisting of: (1) hydrogen,and (2) methyl; or a pharmaceutically acceptable salt thereof.
 2. Acompound which is selected from the group consisting of:N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)ethyl)-2-(2H-1,2,3-triazol-2-yl)benzamide;N-ethyl-N-(2-(4-(2-hydroxybutan-2-yl)-2H-1,2,3-triazol-2-yl)ethyl)-2-(2H-1,2,3-triazol-2-yl)benzamide;N-ethyl-N-(2-(4-(1-hydroxyethyl)-2H-1,2,3-triazol-2-yl)ethyl)-2-(2H-1,2,3-triazol-2-yl)benzamide;2-cyclopropyl-N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)ethyl)benzamide;N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)ethyl)-2-(pyrrolidin-1-yl)benzamide;N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)ethyl)-2-((trifluoromethyl)thio)benzamide;N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)ethyl)-2-(trifluoromethoxy)benzamide;N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-2H-1,2,3-triazol-2-yl)ethyl)-2-isopropoxybenzamide;N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-2-(2H-1,2,3-triazol-2-yl)benzamide;N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-2-(2,2,2-trifluoroethoxy)nicotinamide;N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-2-isopropoxynicotinamide;2-ethoxy-N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)nicotinamide2-(2,2-difluoroethoxy)-N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)nicotinamide;2-(difluoromethoxy)-N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)benzamide;N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-2-(trifluoromethoxy)benzamide;2-ethoxy-N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)benzamide;2-cyclopropyl-N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)benzamide;N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-2-(1H-pyrazol-1-yl)benzamide;N-ethyl-4-fluoro-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-2-(2H-1,2,3-triazol-2-yl)benzamide;N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-2-phenylnicotinamide;N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-2-propylbenzamide;N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-2-(2,2,2-trifluoroethoxy)benzamide;N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-2-(2,2,2-trifluoroethyl)benzamide;2-(2,2-difluoroethoxy)-N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)benzamide;N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-2-(2,2,2-trifluoroethyl)nicotinamide;2-(2,2-difluoroethyl)-N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)benzamide;2-(2,2-difluorocyclopropyl)-N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)benzamide;2-cyclopropyl-N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-6-methoxynicotinamide;2-cyclobutyl-N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)benzamide;N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-2-(pyrrolidin-1-yl)benzamide;N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-2-(2H-tetrazol-2-yl)benzamide;N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-3-(2H-1,2,3-triazol-2-yl)picolinamide;N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-3-phenylpicolinamide;N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-3-(pyridin-2-yl)pyrazine-2-carboxamide;N-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-3-(1H-pyrazol-1-yl)pyrazine-2-carboxamide;andN-ethyl-N-(2-(4-(2-hydroxypropan-2-yl)-5-methyl-2H-1,2,3-triazol-2-yl)ethyl)-2-(1H-pyrazol-1-yl)nicotinamide;or a pharmaceutically acceptable salt thereof.
 3. A pharmaceuticalcomposition which comprises an inert carrier and a compound of claim 1or a pharmaceutically acceptable salt thereof.
 4. A method for enhancingthe quality of sleep in a mammalian patient in need thereof whichcomprises administering to the patient a therapeutically effectiveamount of the compound of claim 1 or a pharmaceutically acceptable saltthereof.
 5. A method for treating insomnia in a mammalian patient inneed thereof which comprises administering to the patient atherapeutically effective amount of the compound of claim 1 or apharmaceutically acceptable salt thereof.